1-Oxadethiacepham compounds

ABSTRACT

Intermediates for preparing an antibacterial 1-dethia-1-oxacephalosporins which are represented by the following formula: ##STR1## wherein R is a monovalent group (minus the carbonyl) from an acyl derived from a carboxylic or carbonic acid; 
     Y 1  is a divalent group of the following formula: ##STR2## wherein COB is carboxy or protected carboxy; 
     X is hydrogen or a nucleophilic group; and 
     Z is a leaving group 
     are prepared from a compound of the following formula: ##STR3## wherein R and Y 1  are as defined above by the action of an acid.

This application is a division of application Ser. No. 374,862, filedMay 4, 1982 (now U.S. Pat. No. 4,443,598), which application is acontinuation-in-part of application Ser. No. 322,662, filed Nov. 18,1981 (now U.S. Pat. No. 4,366,316), which is a continuation ofapplication Ser. No. 72,600, filed Sept. 5, 1979 (now abandoned), whichis a continuation of application Ser. No. 877,811, filed Feb. 14, 1978(now abandoned).

This invention relates to novel 1-dethia-1-oxacepham compounds. Morespecifically, it relates to Compounds I represented by the formula Igiven below, processes for preparing the same, and the use of CompoundsI as new intermediates for preparing potent known antibacterials,1-dethia-1-oxacephalosporins.

INTRODUCTION (Prior art)

Antibacterial 1-dethia-1-oxacephalosporins of the following formula aredescribed by Christensen in the Journal of American Chemical Society,96, 7582 (1974): and by several firms in their patent publications.##STR4## (X is hydrogen, acetoxy, or methyltetrazolylthio). They havebeen prepared as following schemes by several synthetic routes. But,because the reaction proceeds through an intermediary carbonium ion atposition 4 of the azetidinone, the introduction of the oxygen functionthere results in epimeric mixture. This mixture gives about a half ofineffective 6-epimer of desired 1-dethia-1-oxacephalosporin. ##STR5##(wherein A is amino or substituted amino;

COB is carboxy or protected carboxy;

X is hydrogen or nucleophilic group;

Ph is phenyl; and

R' is aryl or alkyl).

DETAILED DESCRIPTION OF THE INVENTION

The first gist of this invention is based on the discovery that thestarting material II, vide infra, cyclizes by the attack of oxygen fromthe reverse side of the ring juncture and results in favorablestereospecific formation of the carbon to oxygen bond. The formedα-RCONH group can be replaced by β-RCONH by introduction of methoxy atposition 7α or through a Schiff base formation, epimerization andhydrolysis, finally giving the desired 1-dethia-1-oxacephalosporinhaving favorable stereochemistry. Other aspects of this invention arethe synthetic processes represented by either one of the followingreaction schemes (1) through (5) and intermediate compounds I given initem (6) below: ##STR6## and

(5) Other modifications on the molecule.

In the above reaction schemes:

A is amino or substituted amino;

E is hydrogen or methoxy;

Y is a divalent group of the following formula: ##STR7## R is amonovalent group (minus the carbonyl function of an acyl group derivedfrom a carboxylic or carbonic acid;

Y¹ is a divalent group Y or ##STR8## COB is carboxy or protectedcarboxy; X is a hydrogen or a nucleophilic group; and

Z is a leaving group.

(6) The compounds of the following formula: ##STR9## wherein A, E and Yare as defined above.

I. COMPOUNDS

The substances provided by this invention are Compounds I represented bythe following formula I: ##STR10## wherein A is amino or substitutedamino;

E is β-hydrogen or α-methoxy; and

Y is a divalent group of the following formula: ##STR11## in which COBis carboxy or protected carboxy;

X is hydrogen or a nucloeophilic group; and

Z is a leaving group.

The amino substituent of the substituted amino group for A can beselected from known side chains of natural or synthetic penicillins orcephalosporins, or their equivalents (e.g. acyl, hydrocarbyl,hydrocarbylidene, organic silyl or sulfenyl groups, or similar aminosubstituent which are conventional in the field of cephalosporin orpenicillin chemistry). There is a wide variation of possible groups Asince they generally have little direct relationship to modification ofthe substituents at other parts of the nucleus.

Said acyl may contain up to 20 carbon atoms and include the followingtypical examples:

(1) C₁ to C₁₀ alkanoyl e.g. formyl, acetyl, propionyl, butyryl,isobutyryl, cyclopropylacetyl, trimethylacetyl, valeryl, t-butylacetyl,caproyl, octanoyl, cyclohexylacetyl, decanoyl, 2-ethylenanthoyl, or likealkanoyl;

(2) C₁ to C₇ haloalkanoyl e.g. chloroacetyl, chloropropionyl,chloroisovaleryl, dichloroacetyl, trichloroacetyl, trichloropropionyl,bromoacetyl, bromopropionyl, dibromocyclohexylcarbonyl, or the likehaloalkanoyl;

(3) azidoacetyl, cyanoacetyl, trifluoromethylthioacetyl,cyanomethylthioacetyl, or (4-pyridon-1-yl)acetyl;

(4) acyl groups of the following formula:

    Ar--CO--

wherein Ar is an aryl e.g. furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl,thiadiazolyl, thiatriazolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,triazinyl, dihydrophenyl, tetrahydrophenyl, tetrahydropyrimidyl,naphthyl, benzothiazolyl, indolyl, quinolyl, isoquinolyl,benzopyrimidyl, cinnolinyl, pyridopyrimidyl, indanyl, or the like aryl,and each is unsubstituted or substituted by a substituent e.g. methyl,ethyl, propyl, hydroxymethyl, chloromethyl, trifluoromethyl, cyano,carboxy, carboxymethyl, aminomethyl, phenyl, chlorophenyl, fluorophenyl,amino, formylamino, acetamido, propionamido, butyrylamino, valeramido,isovaleramido, imino, nitro, hydroxy, methoxy, ethoxy, propoxy,methylenedioxy, ethylenedioxy, formyloxy, acetoxy, propionyloxy,butyryloxy, valeryloxy, phenylacetoxy, benzoyloxy, methanesulfonyloxy,ethanesulfonyloxy, benzenesulfonyloxy, bromobenzenesulfonyloxy,methoxycarbonyloxy, ethoxycarbonyloxy t-butoxycarbonyloxy,benzyloxycarbonyloxy, carbamoyloxy, methylcarbamoyloxy, oxo, chloro,bromo, iodo, or the like substituent;

(5) acyl group of the following formula:

    Ar--CQQ'--CO--

wherein Ar is as defined above and Q and Q' each is hydrogen or methyl;

(6) acyl group of the following formula:

    Ar--G--CQQ'--CO--

wherein Ar, Q, and Q' are as defined above and G is oxygen, sulfur, orimino;

(7) acyl group of the following formula: ##STR12## wherein Ar is asdefined above and T¹ is hydrogen or C₁ to C₆ alkyl e.g. methyl, ethyl,propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl,pentyl, isoamyl, t-pentyl, neopentyl, propylethyl, isopropylethyl, orcyclopentyl;

(8) acyl group of the following formula: ##STR13## wherein Ar is asdefined above and T² is one of (i), (ii), (iii) or (iv) below:

(i) hydroxy or C₁ to C₁₀ acyloxy e.g. formylxoy, acetoxy, propionyloxy,butyryloxy, valeryloxy, cyclopropylacetoxy, cyclopentylpropionyloxy,phenylacetoxy, thienylacetoxy, phenoxyacetoxy, glycolyloxy,glyoxalyloxy, glycyloxy, chloroacetoxy, bromoacetoxy, trifluoroacetoxy,benzoyloxy, methylbenzoyloxy, dimethylbenzoyloxy, nitrobenzoyloxy,methoxybenzoyloxy, cyanobenzoyloxy, methanesulfonylbenzyloxy,carbamoyloxy, methylcarbamoyloxy, ethylcarbamoyloxy, propylcarbamoyloxy,methoxycarbonyloxy, t-butoxycarbonyloxy, benzyloxycarbonyloxy,methoxybenzyloxycarbonyloxy, nitrobenzyloxycarbonyloxy, or like acyls;

(ii) carboxy or protected carboxy as is given later in the explanationof COB;

(iii) sulfo or C₁ to C₅ alkoxysulfonyl e.g. methoxysulfonyl,ethoxysulfonyl, propoxysulfonyl, butoxysulfonyl,cyclopropylmethoxysulfonyl, pentyloxysulfonyl, orcyclopropylethoxysulfonyl; or

(iv) a group of the following formula: ##STR14## in which W¹ and W² eachis hydrogen or a C₁ to C₁₀ amino-substituent, for example, C₂ to C₇alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,t-butoxycarbonyl, pentyloxycarbonyl, or methylhexylcarbonyl; C₃ to C₁₀cycloalkyl-C₂ to C₃ alkoxycarbonyl e.g. cyclopropylmethoxycarbonyl,cyclopropylethoxycarbonyl, cyclopentylmethoxycarbonyl,cyclohexylethoxycarbonyl, or cycloheptylmethoxycarbonyl; C₅ to C₈cycloalkoxycarbonyl e.g. cyclopentylcarbonyl, cyclohexylcarbonyl,cycloheptylcarbonyl, or cyclopropylcarbonyl; C₁ to C₄ -alkylsulfonyl-C₁to C₄ -alkoxycarbonyl e.g. methanesulfonylethoxycarbonyl,ethanesulfonylelthoxycarbonyl, methanesulfonylbutoxycarbonyl, orbutanesulfonylbutoxycarbonyl; halo-C₁ to C₃ -alkoxycarbonyl e.g.chloromethoxycarbonyl, chloroethoxycarbonyl, bromoethoxycarbonyl,iodoethoxycarbonyl, dichloroethoxycarbonyl, trichloroethoxycarbonyl, ortrichloropropoxycarbonyl; aralkoxycarbonyl e.g. benzyloxycarbonyl,methylbenzyloxycarbonyl, dimethylbenzyloxycarbonyl,aminobenzyloxycarbonyl, acetamidobenzyloxycarbonyl,nitrobenzyloxycarbonyl, methoxybenzyloxycarbonyl,chlorobenzyloxycarbonyl, bromobenzyloxycarbonyl,diphenylmethoxycarbonyl, diphenylethoxycarbonyl,thiazolylmethoxycarbonyl, pyridylmethoxycarbonyl, or other Ar--CH₂O--CO-- group (in which Ar is as defined above); C₁ to C₁₀ alkanoyl e.g.formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,t-valeryl, hexanoyl, heptanoyl, cyclohexanecarbonyl, octanoyl,cyclopentanepropionyl, or decanoyl; aromatic acyl of the formulaAr--CO-- in which Ar is as given above; or other acyl group includingpyronecarbonyl, thiopyronecarbonyl, pyridonecarbonyl, carbamoyl,guanidylcarbonyl, ureidocarbonyl, methylimidazolidonecarbonyl,methanesulfonylimidazolidonecarbonyl, methyldioxopiperazin-1-ylcarbonyl,ethyldioxopiperazin-1-ylcarbonyl, and butyldioxopiperazin-1-ylcarbonyl;##STR15## combined together show an enamino or equivalent Schiff basegroup derived from the amine, having amino for T² above, and anenolizable carbonyl compound, for example, C₅ to C₁₀ acetoacetates e.g.methyl, ethyl, propyl, butyl, isobutyl, or pentyl esters of acetoaceticacid, C₅ to C₁₀ acetoacetamides e.g. amide, methylamide, anilide, ormethylanilide of acetoacetic acid, acetylacetone, acetoacetonitrile,α-acetylbutyrolactone, or 1,3-cyclopentanedione; or ##STR16## combinedtogether show a diacylamino derived from a C₄ to C₁₀ dibasic acid e.g.succinimido, maleimido, or phthalimido;

(9) 5-aminoadipoyl; 5-aminoadipoyl protected at the amino group withe.g. C₁ to C₁₀ alkanoyl, aroyl, aralkanoyl, haloalkanoyl, oralkoxycarbonyl as defined hereinabove; or 5-aminoadipoyl protected atthe carboxy group with e.g. alkyl, aryl, aralkyl, or alkylsilyl asdefined hereinbefore;

or

(10) acyl group of the following formula:

    L--O--CO--

wherein L is an easily removable and optionally substituted C₁ to C₁₀hydrocarbyl group e.g. t-butyl, 1,1-dimethylpropyl, cyclopropylmethyl,cyclopropylethyl, 1-methylcyclohexyl, isobornyl, 2-methoxy-t-butyl,2,2,2-trichloroethyl, benzyl, naphthylmethyl, p-methoxybenzyl,p-nitrobenzyl, or pyridylmethyl.

Alternatively, the amino substituent in the group A can be a diacylgroup derived from a C₄ to C₁₀ polybasic carboxylic acid e.g. succinyl,maleoyl, phthaloyl, or pyridine-2,3-dicarbonyl.

Other possible amino substituents in the group A can be a C₁ to C₂₀optionally substituted hydrocarbyl e.g. methyl, ethyl, t-butyl, trityl,methylidene, benzylidene, hydroxybenzylidene, α-halobenzylidene,α-methoxybenzylidene, α-ethoxybenzylidene, 1-methoxy-2-phenylethylidene,3,5-di-t-butyl-4-hydroxybenzylidene, or o-hydroxybenzylidene; C₃ to C₁₀organic silyl e.g. trimethylsilyl, dimethylmethoxysilyl,chlorodimethylsilyl, methyldimethoxysilyl, or methyl ethylenedioxysilyl;or C₁ to C₁₀ sulfenyl e.g. methylthio, phenylthio, or o-nitrophenylthio.

Groups convertible into amino or amido e.g. enamino, amido, azido,isocyanato or isocyano are also included in the scope of group A.

Included in the said definition, the group A can be a cyclic group e.g.4-phenyl-2,2-dimethyl-5-oxoimidazolidin-1-yl,4-p-hydroxyphenyl-2,2-dimethyl-3-nitroso-5-oxoimidazol-idin-1-yl,4-p-hydroxyphenyl-2-phenyl-5-oxoimidazolidin-1-yl, or4-thienyl-5-oxoimidazolidin-1-yl.

The said group A, where possible, can be interrupted by a hetero atom inthe skeleton or can be unsaturated, or can be substituted by, forexample, halogen e.g. fluorine, chlorine, or bromine; a nitrogenfunction e.g. amino, hydrazinyl, azido, alkylamino, arylamino,acylamino, alkylideneamino, acylimino, imino, or nitro; oxygen functione.g. hydroxy, alkoxy, aralkoxy, aryloxy, acyloxy, or oxo; sulfurfunction e.g. mercapto, alkylthio, aralkylthio, arylthio, acylthio,thioxo, sulfo, sulfonyl, sulfinyl, alkoxysulfonyl, or aryloxysulfinyl;carbon function e.g. alkyl, alkenyl, aralkyl, aryl, carboxy, carbalkoxy,carbamoyl, alkanoyl, aroyl, aminoalkyl, aralkanoyl, or cyano; orphosphorus function e.g. phospho or phosphoroyl.

The group B is hydroxy when the group COB is a carboxy group.

Alternatively, the group B can be a carboxy-protecting group. Thus thegroup B can be an oxygen function, for example,

C₁ to C₁₀ alkoxy e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy,t-butoxy, monohydroxy-t-butoxy, methoxy-t-butoxy, cyclopropylmethoxy,pentyloxy, isopentyloxy, cyclopropylethoxy, cyclopentyloxy, hexyloxy,cyclohexyloxy, octyloxy, or decyloxy;

C₁ to C₆ haloalkoxy e.g. chloromethoxy, chloroethoxy, bromoethoxy,iodoethoxy, dichloropropoxy, trichloroethoxy, trichlorobutoxy, ordibromocyclohexyloxy;

C₃ to C₁₀ acylalkoxy e.g. acetonyloxy, acetylethoxy, propionylmethoxy,phenacyloxy, chlorophenacyloxy, bromophenacyloxy, nitrophenacyloxy, ormethylphenacyloxy;

C₃ to C₁₀ alkoxyalkoxy e.g. methoxymethoxy, ethoxymethoxy,chloroethoxymethoxy, propoxyethoxy, butoxyethoxy, cyclohexyloxyethoxy,methoxyethoxymethoxy, butoxyethoxymethoxy, or octyloxyethoxy;

C₂ to C₁₀ aminoalkoxy e.g. aminomethoxy, aminoethoxy,dimethylaminoethoxy, or ethylaminomethoxy;

aryloxy e.g. phenoxy, chlorophenoxy, nitrophenoxy, naphthyloxy,pyridyloxy, indolyloxy, indanyloxy, or pentachlorophenoxy; aralkoxy e.g.benzyloxy, methylbenzyloxy, xylylmethoxy, chlorobenzyloxy,bromobenzyloxy, methoxybenzyloxy, ethoxybenzyloxy, nitrobenzyloxy,dibromobenzyloxy, phenethyloxy, phthalidyloxy,p-hydroxy-di-t-butylbenzyloxy, diphenylmethoxy, or trityloxy; C₁ to C₁₀alkylsilyloxy e.g. trimethylsilyloxy, dimethylmethoxysilyloxy,chlorodimethylsilyloxy, or ethylenedioxymethylsilyloxy; or

C₁ to C₁₀ alkylstannyloxy e.g. trimethylstannyloxy; to form an estergroup;

C₁ to C₁₀ organic or inorganic acyloxy e.g. acetoxy, propionyloxy,sulfonyloxy, sulfooxy, or chloratooxy; to form an anhydride group; or

metaloxy of a group I, II, or III metal in the periodical table e.g.lithiooxy, sodio-oxy, potassio-oxy, or magnesiooxy, or C₁ to C₁₅hydrocarbylammoniooxy e.g. triethylammoniooxy, dicyclohexylammonio-oxyto form a salt group;

a sulfur function, for example, C₁ to C₁₀ hydrocarbylthio or mercapto toform a thiol ester or thiocarboxylic acid group; a nitrogen function,for example,

C₁ to C₅ alkylamino e.g. methylamino, ethylamino, propylamino,butyramino, or pentylamino; or

di-C₁ to C₅ -alkylamino e.g. dimethylamino, diethylamino, piperidyl,morpholin-1-yl, or methylmorpholin-1-yl to form an amide group; or

hydrazinyl or azido group to form hydrazide or azide group.

Usually, the carboxy-protecting groups are removed during the synthesisto give the final objective compounds and wide variety of structure isfeasible without affecting the final product and departing from thisinvention.

The nucleophilic group X can be every possible group being introduced atthe methylene attached to the position 3 of cephem ring in place of theacetoxy group of cephalosporanic acid.

Typical examples of X include halo e.g. chloro or bromo; oxygenfunctions, for example, hydroxy, C₁ to C₄ alkanoyloxy e.g. formyloxy,acetoxy, propionyloxy, or butyryloxy; substituted C₁ to C₄ alkanoyloxye.g. malonyloxy, succinoyloxy, cyanoacetoxy, glycyloxy, alanyloxy,glycolyloxy, glyoxylyloxy, phenoxyacetoxy, sulfopropionyloxy,chloroacetoxy, dichloroacetoxy, or trifluoroacetoxy; aroyloxy e.g.benzoyloxy or naphthoyloxy; carbonic acyloxy e.g. chloroformyloxy,methoxyformyloxy, trichloroethoxyformyloxy, cyclopropylmethoxyformyloxy,or methanesulfonylethoxyformyloxy; C₁ to C₆ alkoxy e.g. methoxy, ethoxy,butoxy, sec-butoxy, cyclopropylmethoxy, or cyclohexyloxy; aralkoxy ofthe formula Ar--CH₂ O-- (in which Ar is as defined above) e.g.benzyloxy, furfuryloxy, or naphthylmethoxy; aryloxy of the formulaAr--O-- (in which Ar is as given above) e.g. phenoxy, naphthyloxy, orindanyloxy; sulfur functions, for example, mercapto, C₁ to C₅alkanoylthio e.g. acetylthio, propionylthio, or butyrylthio; aroylthioe.g. benzoylthio or naphthoylthio; thiocarbamoylthio,methylthiocarbamoylthio; C₁ to C₆ alkylthio e.g. methylthio, ethylthio,propylthio, butylthio, cyclopropylmethylthio, or cyclopropylethylthio;aralkylthio e.g. benzylthio, picolylthio, or phenethylthio; or arylthioof the formula Ar--S-- (in which Ar is as defined above) e.g.phenylthio, triazolylthio, thiadiazolylthio, oxadiazolylthio, ortetrazolylthio, each being unsubstituted or substituted by e.g. methyl,ethyl, hydroxymethyl, hydroxyethyl, carboxyethyl, carboxymethyl,sulfoethyl, dimethylaminoethyl, dimethylaminopentyl, or morpholinoethyl;or nitrogen functions e.g. amino, azido, hydrazinyl, acetylamino,methylamino, pyridinium, picolinium, 4-carboxypyridinium,carbamoylpyridinium, hydroxymethylpyridinium, carboxymethylpyridinium,or chloropyridinium.

Said leaving group Z can be an anionic part of a nucleophilic reagent.Typical examples of them include halo e.g. chloro, bromo, or iodo;hydroxy; or C₁ to C₈ carboxylic acyloxy e.g. acetoxy ortrifluoroacetoxy; sulfonic acyloxy e.g. methanesulfonyloxy,ethanesulfonyloxy, toluenesulfonyloxy, or bromobenzenesulfonyloxy,arylthio e.g. phenylthio, arylsulfenyl e.g. phenylsulfenyl, arylselenyl,arylsulfinyl, or alkylsulfinyl.

The leaving group is removed during the synthesis to give the finalobjective compounds, and wide variety of structure is feasible withoutaffecting on the final product to be produced and without departing fromthis invention.

When R, COB or Y is likely to be affected from undesirable change duringthe reaction, it may be protected in advance and deprotected afterwardsat an optional stage.

The compounds of this invention are shown by the following formula:##STR17## wherein A is amino or substituted amino;

E is hydrogen or methoxy; and

Y is a divalent group of the following formula: ##STR18## in which COBis carboxy or protected carboxy;

X is hydrogen or nucleophilic group; and

Z is a leaving group.

They include compounds of the following formula: ##STR19## wherein A, E,COB, X, and Z are as defined above.

More specific compounds of the m are those in which A is aminosubstituted by:

(1) C₁ to C₁₀ alkanoyl,

(2) C₁ to C₇ haloalkanoyl,

(3) azidoacetyl, cyanoacetyl, trifluoromethylthioacetyl,cyanomethylthioacetyl, or (4-pyridon-1-yl)acetyl;

(4) acyl group of the following formula:

    Ar--CO--

wherein Ar is an aryl selected from furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl,thiadiazolyl, thiatriazolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,triazinyl, dihydrophenyl, tetrahydrophenyl, tetrahydropyrimidyl,naphthyl, benzothiazolyl, indolyl, quinolyl, isoquinolyl,benzopyrimidyl, cinnolinyl, pyridopyrimidyl, or indanyl ring group;

(5) acyl group of the following formula:

    Ar--CQQ'--CO--

wherein Ar is as defined above and Q and Q' each is hydrogen or methyl;

(6) acyl group of the following formula:

    Ar--G--CQQ'--CO--

wherein Ar, Q, and Q' each is as defined above and G is oxygen, sulfur,or imino;

(7) acyl group of the following formula: ##STR20## wherein Ar is asdefined above and T¹ is hydrogen or C₁ to C₆ alkyl;

(8) acyl group of the following formula: ##STR21## wherein Ar is asdefined above and T² is one of (i) hydroxy or C₁ to C₁₀ acyloxy, (ii)carboxy or protected carboxy, (iii) sulfo or C₁ to C₅ alkoxysulfonyl, ora group of the formula: ##STR22## in which W¹ and W² each is hydrogen ora C₁ to C₁₅ amino-substituent;

(9) 5-aminoadipoyl, 5-aminoadipoyl protected at the amino or5-aminoadipoyl protected at the carboxy;

(10) acyl group of the following formula:

    L--O--CO--

wherein L is an easily removable and unsubstituted or substituted C₁ toC₁₀ hydrocarbyl group; or

(11) C₁ to C₂₀ optionally substituted hydrocarbyl, C₃ to C₁₀ organicsilyl, or C₁ to C₁₀ sulfenyl, the group B in said COB is C₁ to C₁₀alkoxy, C₁ to C₆ haloalkoxy, C₃ to C₁₀ acylalkoxy, C₃ to C₁₀alkoxyalkoxy, C₂ to C₁₀ aminoalkoxy, aryloxy, aralkoxy, C₁ to C₁₀alkylsilyloxy, C₁ to C₁₀ alkylstannyloxy, C₁ to C₁₀ acyloxy, inorganicacyloxy, metal-oxy of a group I, II, or III metal in the periodicaltable, C₁ to C₁₅ hydrocarbylammonio-oxy, C₁ to C₁₀ hydrocarbylthio,mercapto, C₁ to C₅ alkylamino, di-C₁ to C₅ alkylamino, hydrazinyl, orazido, the group E is β-hydrogen or α-methoxy;

the group X is halo, hydroxy, C₁ to C₄ alkanoyloxy, substituted C₁ to C₄alkanoyloxy, aroyloxy, carbonic acyloxy, C₁ to C₆ alkoxy, aralkoxy ofthe formula Ar--CH₂ O-- or aryloxy of the formula Ar--O-- (in which Aris as defined above), mercapto, C₁ to C₅ alkanoylthio, aroylthio, C₁ toC₆ alkylthio, aralkylthio of the formula Ar--CH₂ S-- or arylthio of theformula Ar--S-- (in which Ar is as defined above), amino, azido,hydrazinyl, acetylamino, methylamino, pyridinium, picolinium,4-carboxypyridinium, carbamoylpyridinium, hydroxymethylpyridinium,carboxymethylpyridinium, or chloropyridinium, and the group Z is halo,hydroxy or C₁ to C₈ alkanoyloxy, sulfonyloxy, arylthio, arylsulfenyl,arylselenyl, arylsulfinyl, or alkylsulfinyl.

Further specific compounds (I) have benzylamino, methylbenzoylamino,chlorobenzoylamino, nitrobenzoylamino, cyanobenzoylamino,phenoxyacetamido, phenylacetamido,diphenylmethoxycarbonylphenylacetamido, or amino for the A group;hydroxy, benzyloxy, tolylmethoxy, chlorobenzyloxy, diphenylmethoxy,naphthylmethoxy, t-butoxy, or trimethylsilyloxy for B in COB; chloro,bromo, hydroxy, acetoxy, methanesulfonyloxy, methylthio, 1-methyltetrazol-5-ylthio, or hydrogen for the X group; and chloro, bromo,hydroxy, or acetoxy for the Z group.

Some of the specific compounds I are given below:

(1) compounds of the following formula: ##STR23## whereinA=benzoylamino, COB=carboxy, E=β-hydrogen, and X=Z=chloro;

A=benzamido, COB=carboxy, E=β-hydrogen, and X=Z=bromine;

A=benzamido, COB=benzyloxycarbonyl, E=β-hydrogen, and X=Z=chlorine;

A=benzamido, COB=benzyloxycarbonyl, E=β-hydrogen, and X=Z=bromine;

A=benzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen, and X=hydrogen,and Z=hydroxy;

A=benzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen, X=hydrogen, andZ=α-acetoxy;

A=benzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen, X=hydrogen, andZ=bromine;

A=benzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen, and X=Z=hydroxy;

A=benzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen, X=acetoxy, andZ=hydroxy;

A=benzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen, X=hydroxy, andZ=methanesulfonyloxy,

A=benzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen, X=chlorine, andZ=hydroxy;

A=benzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen, andX=Z=chlorine;

A=benzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen, X=methylthio,and Z=chlorine;

A=benzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen,X=1-methyltetrazolylthio, and Z=hydroxy;

A=benzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen, X=1-methyltetrazolylthio, and Z=chlorine;

A=benzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen, X=bromine, andZ=hydroxy;

A=benzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen, and X=Z=bromine;

A=p-methylbenzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen andX=Z=chlorine;

A=p-chlorobenzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen, andX=Z=chlorine;

A=p-cyanobenzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen, andX=Z=chlorine,

A=p-nitrobenzamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen, andX=Z=chlorine;

A=phenoxyacetamido, COB=diphenylmethoxycarbonyl, E=β-hydrogen, andX=Z=chlorine;

A=phenylacetamido, COB=t-butoxycarbonyl, E=β-hydrogen, and X=Z=chlorine;

A=phenylacetamido, COB=benzyloxycarbonyl, E=β-hydrogen, andX=Z=chlorine;

A=benzamido, COB=carboxy, E=α-methoxy, X=hydrogen, and Z=hydroxy;

A=benzamido, COB=carboxy, E=α-methoxy, X=hydrogen, and Z=acetoxy;

A=benzamido, COB=carboxy, E=α-methoxy, X=hydrogen, andZ=trifluoroacetoxy;

A=benzamido, COB=benzyloxycarbonyl, E=α-methoxy, and X=Z=chlorine;

A=benzamido, COB=benzyloxycarbonyl, E=α-methoxy, and X=Z=bromine;

A=benzamido, COB=diphenylmethoxycarbonyl, E=α-methoxy, X=hydrogen, andZ=hydroxy;

A=benzamido, COB=diphenylmethoxycarbonyl, E=α-methoxy, X=hydrogen, andZ=acetoxy;

A=benzamido, COB=diphenylmethoxycarbonyl, E=α-methoxy, X=hydrogen, andZ=trifluoroacetoxy;

A=benzamido, COB=diphenylmethoxycarbonyl, E=α-methoxy, and X=Z=chlorine;

A=benzamido, COB=diphenylmethoxycarbonyl, E=α-methoxy, and X=Z=bromine;

A=p-chlorobenzamido, COB=diphenylmethoxycarbonyl, E=α-methoxy,X=I-methyltetrazolylthio, and X=chlorine;

A=p-cyanobenzamido, COB=diphenylmethoxycarbonyl, E=α-methoxy,X=1-methyltetrazolylthio, and Z=chlorine;

A=p-nitrobenzamido, COB=diphenylmethoxycarbonyl, E=α-methoxy,X=1-methyltetrazolylthio, and X=chlorine;

A=p-methylbenzamido, COB=diphenylmethoxycarbonyl, E=α-methoxy,X=1-methyltetrazolylthio, and Z=chlorine;

A=p-chlorobenzamido, COB=diphenylmethoxycarbonyl, E=α-methoxy, andX=Z=chlorine,

A=p-cyanobenzamido, COB=diphenylmethoxycarbonyl, E=α-methoxy, andX=Z=chlorine,

A=p-nitrobenzamido, COB=diphenylmethoxycarbonyl, E=α-methoxy, andX=Z=chlorine;

A=p-methylbenzamido, COB=diphenylmethoxycarbonyl, E=α-methoxy, andX=Z=chlorine;

A=benzamido, COB=p-methylbenzyloxycarbonyl, E=α-methoxy,X=1-methyltetrazolylthio, and Z=chlorine;

A=benzamido, COB=p-chlorobenzyloxycarbonyl, E=α-methoxy,X=1-methyltetrazolylthio, and Z=chlorine;

A=benzamido, COB=naphthylmethoxycarbonyl, E=α-methoxy,X=1-methyltetrazolylthio, and Z=chlorine; or

A=α-diphenylmethoxycarbonyl-phenylacetamido,COB=diphenylmethoxycarbonyl, E=α-methoxy, and X=Z=chlorine.

Within this group of compounds there may be mentioned compounds of theformula: ##STR24## wherein R¹ is carboxylic acyl;

B is a hydrogen or conventional carboxy protecting group;

E is β-hydrogen or α-methoxy;

X is hydrogen or a nucleophilic group; and

Z is a group of the formula

    RS(O).sub.n --or RSe(O).sub.n --

in which R is C₁ to C₃ alkyl or monocyclic aryl and n is 0, 1 or 2.

(2) compound of the following formula: ##STR25## wherein A=benzamido,COB=carboxy, E=β-hydrogen;

A=benzamido, COB=diphenylmethoxycarbonyl, and E=β-hydrogen;

A=p-methylbenzamido, COB=diphenylmethoxycarbonyl, and E=β-hydrogen;

A=p-chlorobenzamido, COB=diphenylmethoxycarbonyl, and E=β-hydrogen;

A=p-cyanobenzamido, COB=diphenylmethoxycarbonyl, and E=β-hydrogen;

A=p-nitrobenzamido, COB=diphenylmethoxycarbonyl, and E=β-hydrogen;

A=benzamido, COB=benzyloxycarbonyl, and E=β-hydrogen;

A=phenoxyacetamido, COB=diphenylmethoxycarbonyl, and E=β-hydrogen;

A=phenylacetamido, COB=t-butoxycarbonyl, and E=β-hydrogen;

A=phenylacetamido, COB=benzyloxycarbonyl, and E=β-hydrogen;

A=phenylacetamido, COB=diphenylmethoxycarbonyl, and E=β-hydrogen;

A=amino, COB=diphenylmethoxycarbonyl, and E=β-hydrogen;

A=benzamido, COB=diphenylmethoxycarbonyl, and E=α-methoxy;

A=phenylacetamido, COB=benzyloxycarbonyl, and E=α-methoxy;

A=amino, COB=diphenylmethoxycarbonyl, and E=α-methoxy; or

A=amino, COB=benzyloxycarbonyl, and E=α-methoxy.

(3) compounds of the following formula: ##STR26## wherein A=benzamido,COB=diphenylmethoxycarbonyl, and E=β-hydrogen.

(4) compounds of the following formula: ##STR27## wherein A=benzamido,COB=diphenylmethoxycarbonyl, E=β-hydrogen, and X=hydrogen.

Also contemplated within the scope of the present invention arecompounds of the formula: ##STR28## wherein R is C₁ to C₃ alkyl ormonocyclic aryl, e.g., phenyl,

COB is carboxy or protected carboxy, and

Hal is a halogen, e.g., chlorine.

These compounds can be prepared by acylating the corresponding7-amino-3-exomethylene compound with a sulfenic halide RSHal followed byoxidation. After reduction of the 7-thioimino compound to the7-thioamino (RSNH--) compound, such compound can be easily hydrolyzedwith a base or acid in high yield to give the 7-amino compound. Thisprovides a convenient protection procedure for the amino group.

II. USES OF THE COMPOUNDS

Compounds I can be used as starting materials for making knownantibacterials e.g. 1-dethia-1-oxacephalosporins (Japanese PatentPublication (Unexamined) Nos. 49-133,594 and 51-149,295) in high yieldby introducing or migrating a double bond to position 3, replacing Awith an antibacterially preferable side chain, and/or deprotecting theprotected carboxy in COB, if required after introduction ofantibacterially suitable X at the methylene bound to position 3 of1-dethia-1-oxacephem nucleus. Of course, said double bond, A, COB, and Xmay be replaced by antibacterially suitable ones prior to formingdesired cephem ring system. Choice of said groups A, COB, and X in thestarting materials and the intermediates depends mainly on easiness ofreactions, stability under reaction conditions, and on the factors ofwaste, costs, or other practical and technical factors.

Compounds (1) can be, for example, subjected to (a) HZ-elimination togive a 1-dethia-1-oxacephalosporin (4) which can also be prepared by (b)double bond migration of Compound (2) with a base (e.g. triethylamine)at 0° C. to 70° C. for 5 hours to 3 days or by (c) cyclization ofCompound (3) with a Lewis acid (e.g. boron trifluoride) at 0° C. to 50°C. for 0.1 to 1 hour. All of the processes (a), (b), and (c) can beeffected under conditions analogous to the corresponding treatmentsgiven later in relation to the compounds of this invention. Some ofillustrative examples are given below in the working examples. ##STR29##(wherein A, COB, X and Z are as given above and

R means a group of acyl (minus the carbonyl function) when A is anα-amino function represented by RCONH)

Compounds I (A=7β-amido; COB=COOH) or pharmaceutically acceptable saltsthereof are moderately active antibacterials. They can be injected witha conventional carrier to a patient suffering from bacterial infectioncaused by sensitive gram positive bacteria (e.g. Streptococcus pyogenes)or gram negative bacteria (e.g. Escherichia coli) at a dose of 0.1 to 10g per day.

III. PROCESSES

The said Compounds I are prepared in several synthetic routes as givenbelow with reaction scheme: ##STR30## and

(5) Other modification on the molecule. In these reaction schemes, R,Y¹, A, E, COB, X and Z are as defined hereinbefore.

Detailed explanation of thee processes are given below.

(1) Cyclization

Compounds Ia (wherein A is an α-RCONH and E is β-hydrogen) arepreparable from the corresponding Oxazolinoazetidine II under the actionof an acid according to the following reaction scheme: ##STR31## In theabove formulas R is a monovalent group (minus the carbonyl function)from an acyl derived from a carboxylic or carbonic acid;

Y¹ is a divalent group of the following formula: ##STR32## in which COBis carboxy or protected carboxy;

X is hydrogen or a nucleophilic group; and

Z is a leaving group.

The group R corresponds to the monovalent group of acyl (minus thecarbonyl function) derived from carboxylic or carbonic acyls as definedin the Section I Compounds.

Compounds Ia may be prepared from the corresponding OxazolinoazetidinesII by treating with an acid. Typical examples of the acid includemineral acids (e.g. HCl, HBr, HNO₃, H₂ SO₄, or H₃ PO₄), sulfonic acids(e.g. CH₃ SO₃ H, C₂ H₅ SO₃ H, C₆ H₅ SO₃ H, CH₃ C₆ H₄ SO₃ H, BrC₆ H₄ SO₃H, CF₃ SO₃ H, or naphthalenesulfonic acid) strong carboxylic acids (e.g.Cl₃ CCOOH, CF₃ COOH), Lewis acids (e.g. BF₃, ZnCl₂, SnCl₂, SnCl₄, SnBr₂,SbCl₃, SbCl₅, or TiCl₃), and similar acids.

The reaction is complete usually within 5 minutes to 10 hours, often 15minutes to 3 hours at -30° C. to +50° C., especially at 15° C. to 30°C., to give Compounds Ia in high yield. If required, the reaction can becarried out with stirring or under an inert gas (e.g. nitrogen, argon,carbon dioxide) atmosphere.

The reaction is generally carried out in an inert solvent. Typical inertsolvents include hydrocarbons (e.g. hexane, cyclohexane, benzene,toluene), halohydrocarbons (e.g. methylene chloride, chloroform,dichloroethane, carbon tetrachloride, chlorobenzene), ethers (e.g.diethyl ether, diisobutyl ether, dioxane, tetrahydrofuran), esters (e.g.ethyl acetate, butyl acetate, methyl benzoate), ketones (e.g. acetone,methyl ethyl ketone, cyclohexanone), sulfoxides (e.g. dimethylsulfoxide), nitriles (e.g. acetonitrile, benzonitrile), and likesolvents and mixtures thereof. Solvents having hydroxy function mayreact with the starting materials II to give by-products, but they alsoare available under controlled reaction conditions. Typical examples ofsuch hydroxy-solvents are water, alcohols (e.g. methanol, ethanol,t-butanol, benzyl alcohols), acids (e.g., formic acid, acetic acid,propionic acid), and mixtures thereof.

The terminal hydroxy linked to Y¹ on Oxazolinoacetidine II may beprotected in advance by a hydroxy-protecting group (e.g. formyl,tetrahydropyranyl, or the like) readily removable under the reactionconditions.

Occasionally, double bond migration, introduction of a nucleophile,elimination or like side reaction takes place during the reaction, butthe side reactions can be also used intentionally for better proceduresto be included in this invention.

In a typical example, an Oxazolinoazetidine II (one part) is dissolvedin a mixture of 5 to 10 parts of halohydrocarbon (e.g. chloroform,dichloromethane), and 0 to 10 parts of ether solvent (e.g. ether,dioxane), mixed with 1 to 0.001 molar equivalent of an acid (e.g. borontrifluoride etherate, toluenesulfonic acid, copper sulfate, zincchloride, stannic chloride), and the solution is kept at 10° to 60° C.for 0.5 to 10 hours to give the corresponding Compound Ia in about 50 to95% yield.

Said Oxazolinoazetidines II are prepared from 6-epi-penicillin-1-oxidese.g. according to the following reaction sequences: ##STR33## (whereinR, COB, and X are as defined above)

(2) Methoxylation

Transformation of said group E from hydrogen to methoxy in compounds Iacan be done stepwise as follows: at first, the part --NH-- in the sidechain A is oxidized to form an imino --N═ on the corner at position 7,then equimolar methanol is added to the imino to reform another --NH--linkage and a methoxy in place of the original hydrogen.

When the A group is amino or amido, starting Compound Ia is treated withan N-halogenating reagent, subjected to hydrogen halide elimination witha base to give corresponding imino compound, and then treated withmethanol to give the objective Compound Ia (where E is α-methoxy). Bysuch an N-halogenation, other part of the molecule may be partiallyhalogenated, but the over-halogenated product may be reduced to removeexcessively introduced halogen atom. The procedures may be one of thefollowings:

(1) reaction of amine or amide with an N-halogenating reagent (e.g.molecular halogen, t-butyl hypochlorite), followed by the action ofalkali metal methoxide (e.g. lithium methylate, sodium methylate,potassium methylate) or alkaline earth metal methoxide [e.g. Mg (OCH₃)₂,Ca(OCH₃)₂, Ba(OCH₃)₂ or like base] in methanol;

(2) reaction with t-butyl hypohalite and methanol in the presence of abase and phenyllithium, if required, with an additional solvent (e.g.tetrahydrofuran);

(3) the reaction with t-butyl hypohalite in the presence of sodiumborate in methanol, and when an over-halogenated product if partiallyformed, the product is subjected to reduction with zinc, phosphite, orthe like; and

(4) successive treatments with bromine-DBU, phosphoruspentachloride-pyridine, base, methanolic base, and trialkylsilylchloride or tetraalkylammonium chloride. Alternatively, CompoundsIa(E=H, A=NH₂) can be treated with a suitable aldehyde (e.g.benzaldehyde, p-hydroxybenzaldehyde,3,5-di-t-butyl-4-hydroxybenzaldehyde) to form a Schiff base, oxidized togive an imino compound, treated with methanol, and then hydrolyzed togive other Compounds Ia (E=OCH₃, A=NH₂).

In a typical example, 1 part of the amide Ia is dissolved in 10 to 50parts of an inert solvent (e.g. dichloromethane, dioxan, ether, dipropylether, tetrahydrofuran), stirred with 1 to 5 mole equivalents ofN-halogenating reagent (e.g. molecular halogen in carbon tetrachlorideor t-butyl hypochlorite) for 2 to 10 minutes at -70° C. to -10° C.,mixed with 1 to 4 equivalents of a metal methoxide (e.g. lithiummethoxide, magnesium methoxide) in methanol, and stirred at -50° C. to0° C. for 5 to 70 minutes. The reaction mixture is neutralized withacetic acid or mineral acid, and the product is extracted with anorganic solvent. Such a treatment gives usually up to 95% yield ofobjective Compound Ia(E=OCH₃).

(3) Addition

A compound I having an exomethylene group at position 3 reacts easilywith an addition reagent XZ (e.g. molecular halogen, peracid, peroxide,hypohalite salt, hypohalite ester, heavy metal peroxide such as osmiumtetroxide, sulfenyl halide) in an inert solvent (e.g. hydrocarbon,halohydrocarbon, ether, ester, or like solvents) to give newer CompoundsI where Y is a divalent group of the formula: ##STR34## (in which COB,X, and Z are as defined above).

The addition may be accomplished smoothly even at low temperature of-70° C. to 0° C. for 5 minutes to 10 hours in an inert solvent(especially halohydrocarbon and ether solvents) giving up to 90% yieldof the addition product owing to high reactivity of exomethylene-doublebond at position 3. When the reagent is a molecular halogen, thehalogenation can be accelerated under the irradiation of light or theaddition of a catalyst (e.g. Cu, Cu₂ S, Cu₂ Cl₂, Ph₃ PO) to give ahigher addition yield.

(4) Elimination to give 1-dethia-1-oxacephlosporins

This step is carried out by removing Z from the starting compound Ialong with a neighbouring hydrogen to give Δ² - or Δ³ -cephem compounds.The double bond formation depends on the location of the eliminatedhydrogen, but the isomerism may be also a result of migration offormerly formed double bond under the reaction condition or duringwork-up.

When the reactivity of Z is high enough, HZ is easily eliminated withoutany other reagent e.g. by keeping the Compund I at an elevatedtemperature.

When Z is halo (e.g. chloro, bromo, iodo) or acyloxy (e.g. mineral acidacyloxy, optionally substituted alkanoyloxy, carbamoyloxy, sulfonyloxy,phosphoryloxy), the elimination is accelerated by addition of anacid-acceptor (e.g. aliphatic amine, aromatic base; salt of weak organicacid and strong base; alkali metal hydroxide, bicarbonate, carbonate,mercaptide, or alcoholate; alkaline earth metal oxide, hydroxide,hydrogencarbonate, or carbonate; alumina, silica gel).

When Z is hydroxy, the elimination is accelerated by addition of adehydrating reagent (e.g. phosphorus pentoxide, mineral acid, Lewisacid, strong carboxylic acid, aliphatic or aromatic sulfonic acid orphosphonic acid, inorganic or organic base, alumina, silica gel, amide),halogenating reagent (e.g. phosphorus pentahalide, phosphorus trihalide,phosphorus oxyhalide, thionyl halide, sulfuryl hlide), acylating reagent(e.g. acid anhydride, acid halide, acid isocyanide) or like reagent, ifrequired in the presence of an acid-acceptor (e.g. said acid acceptorgiven above).

The reaction can be carried out at -50° C. to 100° C. with stirringunder inert gas (e.g. nitrogen, argon, or carbon dioxide) in a solvent(e.g. said hydrocarbon, halohydrocarbon, ether, ester, ketone, alciohol,sulfoxide, or nitile solvent; base such as pyridine or quinoline; acid;acid anhydride such as acetic or trifluoroacetic anhydride; or likesolvents or mixtures thereof).

(5) Other modifications

Compounds I are found to be the subject of other structuralmodifications conventional in the β-lactam chemistry (e.g. double bondmigration with a base, protection and deprotection at the carboxy groupfor COB, protection and deprotection at the amino group for group A,introduction or replacement of group X with a nucleophilic reagent, ortransformation of group X or Z within the given definition includingacylation, hydrolysis, oxidation, or reduction, and like modifications)to give another Compound I, as are evidenced by working Examplesdescribed later.

The said reactions can be carried out in a hydrocarbon solvent (e.g.hexane, toluene), halohydrocarbon (e.g. dichloromethane, chlorobenzene),ether (e.g. diethyl ether, dioxane), ketone (e.g. acetone,cyclohexanone, benzophenone), ester (e.g. ethyl acetate, methylbenzoate), alcohol (e.g. ethanol, t-butanol, benzyl alcohol), amide,carboxylic acid, or other conventional solvents for organic reactions.(Utilizing side reactions)

When the original molecule contains reactive groups, it may beoccasionally attacked by the reagent or solvent during the said reactionor work-up. For example, addition of halogen to 3-exomethylene groupaccompanies N-halogenation in 7-amide chain; imino formation with a basefor 7-methoxy introduction causes HZ elimination when Z is halo oracyloxy; and replacement of X being halo with basic nucleophilic reagentresults in HZ elimination when Z is halo. These can be deemed usually asside-reactions, but when such side-reactions are used in the rightdirection more efficient synthesis can be done than conventionalstep-by-step reaction procedures.

Typical plans of such wise solutions are given in the working examplesbelow. These multi-phase improvements should be included in the scope ofthis invention, allotting to each of the unit changes found in themolecule. (Isolation and purification of the products)

Compounds I thus prepared by cyclization, methoxylation, addition,elimination, or other modifications can be isolated from the reactionmixture by removing the used solvent, unreacted materials, by-products,and like contaminants by concentration, extraction, washing, drying orlike usual methods, and purified by reprecipitation, chromatography,crystallization, absorption, or like conventional purification. Thestereoisomers at position 3 or 7 can be separated by carefulchromatography, fractional recrystallization, or like conventionalmethod. If desirable, stereoisomeric mixture may be subjected toreaction of next step of synthesis without separation.

IV. ADVANTAGES OF THE PROCESSES OVER PRIOR ART

The known method for preparing 1-dethia-1-oxacephalosporins starts froma penicillins (Japanese Patent Publication (Unexamined) No. 51-149295)by cleaving the thiazolidine ring, making azetidinone thiol naked, andrebinding new alcohol units to form azetidinooxazine bicycle. Anothertotal synthesis (Japanese Patent Publication (Unexamined) No. 49-133594)requires more difficult intermolecular cyclization to form thedihydrooxazine ring. This invention aims at no carbon loss from startingpenicillins, resulting in smoother intramolecular cyclization and lessby-products, to give higher yield of expected Compound I and1-dethia-1-oxacephalosporins.

Because of intermediacy of carbonium ion at position 4 in the startingazetidinone, prior art-methods result in the formation of an isomericmixture of 4α and 4β ethers in around 1:1 ratio, followed by undesiredloss of about a half of the ether product. This invention relates tostereoselective synthesis and is accompanied by practically none of suchstereoisomers being lost.

As a result of the stereospecific reactions in high yield, products arereadily crystallizable after simpler purification.

The following examples illustrate details of this invention, but theyare not intended to limit the scope thereof.

The common nuclei and their numbering of compounds in the examples areshown as follows: ##STR35## 1βH,5βH-or(1R,5S)-7-oxo-4-oxa-1-dethia-1-oxacepham2,6-diazabicyclo[3.2.0]hept-2-ene

The stereochemical relationship carbons 1 and 5 in the bicyclohept-2-eneis directly transfered to the configurations of carbons 6 and 5 in6-epipenicillins or carbons 7 and 6 in oxacephams, respectively.

The stereochemistry around carbon 6 of 1-dethia-1-oxacepham ring systemis identical with carbon 6 of cephalosporins at position 6.

Stereochemistry of COB in the formulae is preferably the same with thatin penicillins (i.e. R configuration) but not necessarily restricted toit.

In the following Examples, experimental errors in IR-spectra are within±10 cm⁻¹ and those in NMR spectra are within ±0.2 ppm. Melting pointsare uncorrected. Anhydrous sodium sulfate was used for drying everysolution.

Physical constants of the products are summarized in Table VI.

I. CYCLIZATION

EXAMPLES I-1 TO 32

An Oxazolinoazetidine (II) is dissolved in a solvent and mixed with anacid to give an 1-dethia-1-oxacepham compound (I) under a conditionshown in Table I.

Details of reaction No. 13 are given below to show typical experimentalprocedure of the cyclization. ##STR36##

(1) A solution of diphenylmethyl2-[(1R,5S)-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl]-2-isopropenylacetate(12.0 g), osmium tetroxide (1.0 g) and potassium chlorate (12.0 g) in amixture of tetrahydrofuran (400 ml) and water (200 ml is stirred at 58°C. for 3.5 hours. After cooling, the reaction mixture is poured intoice-water and extracted with ethyl acetate. The extract is washed withbrine, aqueous 10% sodium thiosulfate and then aqueous sodiumhydrogencarbonate, dried and evaporated to yield diphenylmethyl2-[(1R,5S)-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl]-3,4-dihydroxy-3-methylbutyrate(12.88 g).

IR: ν_(max) ^(CHCl).sbsp.3 3500br, 1770br, 1742, 1636 cm⁻¹.

(2) To a solution of the product (10.88 g) prepared above (1) in diethylether (300 ml) is added boron trifluoride etherate (75 μl), and themixture is stirred for 3.5 hours at room temperature under nitrogenatmosphere, poured into cold aqueous sodium hydrogencarbonate, andextracted with ethyl acetate. The extract is washed with brine andevaporated. The residue is washed with a mixture of dichloromethane andether to yield a mixture (15 g) of isomers at position 3 ofdiphenylmethyl7α-benzamido-3ξ-methyl-3ξ-hydroxy-1-dethia-1-oxacepham-4.alpha.-carboxylate.

IR: ν_(max) ^(CHCl).sbsp.3 3560, 3445, 1774, 1739, 1670 cm⁻¹.

The isomeric mixture is chromatographed on a column of silica geldeactivated with 10% water. Eluate with a mixture (4:1) of benzene andethyl acetate is recrystallized from a mixture of acetone and ether andthen a mixture of acetone and dichloromethane to give those respectivetwo stereoisomers.

EXAMPLE I-33 ##STR37##

(a) To a solution of benzyl2-[(1R,5S)-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)]-3-formyloxymethyl-2-butenoate(54 mg) in methanol (2 ml) is added boron trifluoride etherate (19 μl)under cooling at -20° C., and the mixture stirred at -20° C. to 0° C.for 40 minutes, at 0° C. for 2 hours, and then at room temperature for 1hour, mixed with aqueous 5% sodium hydrogencarbonate and extracted withdichloromethane. The extract is washed with water, dried, andevaporated. The residue is crystallized from methanol to afford benzyl7α-benzamido-3-methyl-1-dethia-1-oxa-3-cephem-4-carboxylate (10 mg=20%yield).

mp. 208°-212° C.

(b) In a manner similar to the above but using trifluoromethanesulfonicacid (5 μl) for 130 minutes under ice-cooling or 0.38N hydrogen chloridein methanol (0.5 ml) for 3 hours, instead of boron trifluoride, the sameproduct (14 mg or 5 mg) is also prepared (27.5% or 7% yield).

mp. 208°-212° C.

II. METHOXYLATION

EXAMPLES II-1 TO 24

A 7β-unsubstituted-7α-amido-1-dethia-1-oxacepham compound (I) isdissolved in a solvent, and mixed with an N-halogenating reagent and abase in methanol under a condition given in Table II to give thecorresponding 7α-methoxh-7β-amido compound.

Details of reactions No. 5 and No. 9 are given below to showexperimental procedure of the methoxylation.

(No. 5)

To a solution of diphenylmethyl7α-benzamido-3α-hydroxy-3β-methyl-1-dethia-1-oxacepham-4.alpha.-carboxylate(486 mg) in anhydrous dichloromethane (20 ml) are added t-butylhypochlorite (0.15 ml) and 2N solution of lithium methoxide in methanol(1.1 ml) at -50° C., and the mixture is stirred for 15 minutes, mixedwith acetic acid (1.2 ml), stirred for 5 minutes, diluted withice-cooled aqueous sodium hydrogencarbonate, and extracted with dichloromethane. The extract is washed with aqueous sodium hydrogen-carbonateand water, dried, and evaporated. The colorless foamy residue ispurified by chromatography on silica gel to give diphenylmethyl7β-benzamido-7α-methoxy-3α-hydroxy-3β-methyl-1-dethia-1-oxacepham-4α-carboxylate(250 mg=48% yield). ##STR38##

To a solution of diphenylmethyl7α-benzamido-3ξ-bromo-3ξ-bromoethyl-1-dethia-1-oxacepham-4.alpha.-carboxylate(187 mg) in anhydrous dichloromethane (1 ml) are added t-butylhypochlorite (46 μ) and 2M solution of lithium methylate in methanol(0.17 ml) at -30° C., and the mixture is stirred at the same temperaturefor 1 hour, mixed with a solution of sodium1-methyltetrazol-5-ylmercaptide (100 mg) in acetone (1 ml) and stirredat room temperature for 1.5 hours. The reaction mixture is diluted withdichloromethane, washed with aqueous sodium hydrogencarbonate and brine,dried, and evaporated. The residue (180 mg) is chromatographed on acolumn of silica gel. Eluates with a mixture (1:1) of benzene and ethylacetate give diphenylmethyl7β-benzamido-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate(108 mg).

III. ADDITION

EXAMPLES III-1 TO 16

A 3,3-methylene-1-dethia-1-oxacepham compound (I) is dissolved in asolvent, mixed with an addition reagent XZ under conditions shown inTable III to give an addition product.

Details of those reactions No. 3, No. 4, and No. 15 are given below toshow experimental procedure of the addition. ##STR39##

(No. 3)

To a solution of diphenylmethyl7α-benzamido-3-exo-methylene-1-dethia-1-oxacepham-4α-carboxylate (519mg) in dichloromethane (5 ml) is added 0.76N solution of chlorine incarbon tetrachloride (1.6 ml), and the mixture is stirred underirradiation with a tungsten lamp at -20° to -30° C. for 40 minutes,mixed with 0.14 ml of cyclopentene, and stirred for 5 minutes.

The reaction mixture is stirred with 0.14 ml of1,5-diazabicyclo[3.4.0]non-5-ene at -20° C. for 10 minutes, washed withdilute hydrochloric acid and water, dried, and evaporated. Thecrystalline residue is recrystallized from methanol to givediphenylmethyl7α-benzamido-3-chloromethyl-1-dethia-1-oxa-3-cephem-4-carboxylate (484mg=86% yield). mp. 120°-128° C.

(No. 4)

To a solution of diphenylmethyl7α-benzamido-3-methylene-1-dethia-1-oxacepham-4α-carboxylate (103 mg) inmethylene chloride (1 ml) is added 0.75N solution of chlorine in carbontetrachloride (0.3 ml), and the mixture is irradiated with tungsten lampat -20° to -30° C. for 30 minutes, and evaporated under reduced pressureto give diphenylmethyl7α-benzamido-3ξ-chloro-3ξ-chloromethyl-1-dethia-1-oxacepham-4.alpha.-carboxylate(120 mg).

(No. 15)

In a manner similar to the above, diphenylmethyl7α-phenylacetamido-3-methylene-1-dethia-1-oxacepham-4α-carboxylate (705mg) is reacted with 1.77 equivalents of chlorine in dichloromethane (7ml) at a temperature below -25° C. to give diphenylmethyl7α-phenylacetamido-3ξ-chloro-3ξ-chloromethyl-1-dethia-1-oxacepham-4α-carboxylate.

The latter is treated with piperidine (0.16 ml) at 15° C. for 40 minutesto yield diphenylmethyl7α-phenylacetamido-3-chloromethyl-1-dethia-1-oxa-3-cephem-4-carboxylate(586 mg=78.4% yield) mp. 179°-182° C. (decomposition).

EXAMPLE III-17 ##STR40##

To a solution of diphenylmethyl7α-benzamido-3-methylene-1-dethia-1-oxacepham-4α-carboxylate (1.405g=3.0 mmoles) in dry dichloromethane (28 ml) cooled at -26° C. is addedpowdered copper (141 mg) with stirring under nitrogen atmosphere and themixture is dropwise mixed with 1.2M solution of chlorine in chloroform(6.3 ml=2.5 equivalents) during 10 minutes, and stirred at -22° to -30°C. for 3 hours. The reaction mixture is mixed with an aqueous solutionof sodium thiosulfate pentahydrate (2.98 g=4 equivalents), extractedtwice with dichloromethane, washed with aqueous sodiumhydrogencarbonate, washed twice with aqueous sodium chloride, dried overmagnesium sulfate and evaporated. The residue is chromatographed over190 g of silica gel and eluted with a mixture of benzene and ethylacetate (3:1) to give colorless foamy diphenylmethyl7α-benzamido-3α-chloro-3β-chloromethyl-1-dethia-1-oxacepham-4α-carboxylate(1.541 g=95.2% yield).

IV. ELIMINATION

EXAMPLE IV-1 TO 20

A 1-dethia-1-oxacephem compound is dissolved in a solvent and mixed withan eliminating reagent under conditions shown in Table IV to give a1-dethia-1-oxacephem compound (I).

Details of reaction No. 12 are given below to show experimentalprocedure of the elimination. ##STR41##

To a suspension of diphenylmethyl7α-benzamido-3ξ-hydroxy-3ξ-methyl-1-oxadethiacepham-4α-carboxylate (15.0g) in dichloromethane (100 ml) are added pyridine (6.8 ml) and thionylchloride (3 ml) with stirring under ice-cooling, and the mixture isstirred for 7.25 hours at the same temperature and for 2.25 hours atroom temperature, and poured into ice-water. The organic layer isseparated, washed with water, dried, and evaporated. The residue ischromatographed on silica gel (350 g) deactivated with 10% water. Eluatewith a mixture (9:1) of benzene and ethyl acetate gives diphenylmethyl7α-benzamido-3-methyl-1-dethia-1-oxa-3-cephem-4-carboxylate (2.65g=25.2% yield) (mp. 144°-146° C.) and diphenylmethyl7α-benzamido-3-methyl-1-dethia-1-oxa-2-cephem-4α-carboxylate (1.05g=10.8% yield)

(IR: ν_(max) ^(CHCl).sbsp.3 3440, 1782, 1745, 1676, 1663sh cm⁻¹).

V. CONTINUOUS PROCESS

EXAMPLE V-1 TO 8

A7α-amino-7β-unsubstituted-3-exomethylene-1-dethia-1-oxacepham-4-carboxylateis dissolved in dichloromethane, mixed with a halogenating reagent and abase in methanol to give a3-halo-3-halomethyl-7α-methoxy-7β-amino-1-dethia-1-oxa-3-cephem-4-carboxylateunder conditions given in Table V. Occasionally, 3-halogenomethyl isreplaced by another nucleophile.

Details of Example V-6 are given below to show experimental procedure ofthe continuous process of addition, methoxylation, and elimination.##STR42##

To a solution of diphenylmethyl7α-p-cyanobenzamido-3-exomethylene-1-dethia-1-oxacephem-4α-carboxylate(246 mg) in dichloromethane (8 ml) cooled at -50° C. is added 1.2Msolution of chlorine in carbon tetrachloride (1.47 ml) and the mixtureis stirred under irradiation with 300 W tungsten lamp for 7 minutes. Tothe reaction mixture containing thus formed diphenylmethyl7α-(N-chloro-p-cyanobenzamido)-3-exomethylene-1-dethia-1-oxacepham-4α-carboxylate2M solution of lithium methoxide in methanol (1.57 ml) is added, and thewhole mixture is cooled at -50° C. to -60° C. with stirring for 10minutes, added acetic acid (0.2 ml), poured into ice-water, andextracted with dichloromethane. The extract is washed with diluteaqueous sodium hydrogen carbonate and water, dried, and evaporated todryness. The residue contains diphenylmethyl7α-cyanobenzamido-7α-methoxy-3-chloro-methyl-1-dethia-1-oxa-3-cephem-4-carboxylate.It is dissolved in dichloromethane (6 ml) with stirring with sodium1-methyltetrazol-5-mercaptide (100 mg) and tetrabutylammonium bromide(20 mg) in water (3 ml) at room temperature for 1 hour. The reactionmixture is poured into ice-water, extracted with dichloromethane, washedwith water, dried, and evaporated to leave 335 mg of residue which givespurer7β-p-cyanobenzamido-7α-methoxy-3-(1-methyltetrazol-5-ylthio)methyl-1-dethia-1-oxa-3-cephem-4-carboxylate(251 mg) after silica gel-column chromatography.

A. DOUBLE BOND MIGRATION

EXAMPLE A-1

To a solution of7β-benzamido-7α-methoxy-3-methyl-1-dethia-1-oxa-2-cephem-4-carboxylicacid (100 mg) in acetone (10 ml) is added triethylamine (0.1 ml), andthe mixture allowed to stand for 6 days. Spots of the reaction mixtureon thin layer chromatogram correspond to those of7β-benzamido-7α-methoxy-3-methyl-1-dethia-1-oxa-3-cephem-4-carboxylicacid and of the starting material.

EXAMPLE A-2

To a solution of diphenylmethyl7α-benzamido-3,3-methylene-1-dethia-1-oxacepham-4α-carboxylate (5.0 g)in dichloromethane (25 ml) is added triethylamine (0.5 ml), and themixture is stirred at room temperature for 80 minutes, concentratedafter addition of small amount of benzene, and diluted with ether togive crystals of diphenylmethyl7α-benzamido-3-methyl-1-dethia-1-oxa-3-cephem-4-carboxylate (4.5 g=90%yield).

The mixture is kept in equilibrium at room temperature for 15 hours togive 50.8% of Δ² -isomer, 4.1% of a mixture of Δ² and Δ³ -isomers, and38.3% of Δ³ -isomer after chromatographic separation.

EXAMPLE A-3

To a solution of7α-benzamido-3,3-methylene-1-dethia-1-oxacepham-4α-carboxylic acid (100mg) in acetone (10 ml) is added triethylamine (0.1 ml), and the mixtureis allowed to stand for 5 days. Spots of the reaction mixture correspondto those of 7α-benzamido-3-methyl-1-dethia-1-oxa-2-cephem-4-carboxylicacid, 7α-benzamido-3-methyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid,and the starting material.

B. REMOVAL OF CARBOXY-PROTECTING GROUP

EXAMPLE B-1

To a solution of diphenylmethyl7β-benzamido-7α-methoxy-3α-methyl-3β-acetoxy-1-dethia-1-oxacepham-4α-carboxylate(960 mg) in anisole (4 ml) is added trifluoroacetic acid (10 ml) at 0°C., and the mixture is stirred for 15 minutes and evaporated underreduced pressure. The residue is solidified from a mixture of ether andn-hexane to yield7β-benzamido-7α-methoxy-3α-methyl-3β-acetoxy-1-dethia-1-oxacepham-4α-carboxylicacid (470 mg) as colorless powder (70% yield). mp. 203°-208° C.(decomposition).

In a similar manner, the following free carboxylic acids at position 4are prepared from the corresponding diphenylmethyl esters.

7β-Benzamido-7α-methoxy-3α-hydroxy-3β-methyl-1-dethia-1-oxacepham-4α-carboxylicacid, mp. 100°-105° C. (decomposition).

7α-Benzamido-7α-methoxy-3α-trifluoroacetoxy-3β-methyl-1-dethia-1-oxacepham-4α-carboxylicacid, mp. 108°-113° C.

7β-Benzamido-7α-methoxy-3-methyl-1-dethia-1-oxa-2-cephem-4-carboxylicacid, mp. 195°-198° C.

IR: ν_(max) ^(KBr) 3250, 1766, 1742, 1642 cm⁻¹.

7α-Benzamido-3ξ-chloro-3ξ-chloromethyl-1-dethia-1-oxa-cepham-4.alpha.-carboxylicacid, mp. 118°-122° C. (decomposition).

EXAMPLE B-2

To a solution of diphenylmethyl7α-benzamido-3-exo-methylene-1-dethia-1-oxacepham-4α-carboxylate (1.125g) in a mixture of dichloromethane (15 ml) and anisole (3.5 ml) is addeddropwise a solution of aluminum trichloride (625 mg) in nitromethane (20ml) at -20° C. with stirring, and the mixture is stirred at -10° to -20°C. for 30 minutes under nitrogen atmosphere. The reaction mixture ispoured into ice-water containing hydrochloric acid and extracted withethyl acetate. The extract solution is washed with saturated aqueoussodium hydrogen carbonate, and the washings are acidified withconcentrated hydrochloric acid and reextracted with ethyl acetate. Theorganic layer is washed with water, dried and evaporated to leave7α-benzamido-3-exomethylene-1-dethia-1-oxacepham-4α-carboxylic acid (623mg).

Similarly, diphenylmethyl7α-benzamido-3-methyl-1-dethia-1-oxa-2-cephem-4α-carboxylate (1.8 g) indichloromethane (25 ml) is subjected to solvolysis with anisole (5.8ml), aluminum trichloride (1.026 g), and nitromethane (36 ml) at -10° C.for 30 minutes to give7α-benzamido-3-methyl-1-dethia-1-oxa-2-cephem-4α-carboxylic acid (935mg=72.6% yield).

C. PROTECTION AND DEPROTECTION OF AMINO GROUP

EXAMPLE C-1

To a solution of diphenylmethyl7α-amino-3-methylene-1-dethia-1-oxacepham-4α-carboxylate (25 mg) indichloromethane (0.5 ml) are added pyridine (7 μl) and benzoyl chloride(10 μl) at -20° C. under nitrogen atmosphere, and the mixture is stirredfor 1 hour, poured into ice-water, stirred for 5 minutes, and extractedwith dichloromethane. The organic layer is separated, washed with water,aqueous sodium hydrogencarbonate and water, dried, and evaporated togive diphenylmethyl7α-benzamido-3-methylene-1-dethia-1-oxacepham-4α-carboxylate (28 mg=86%yield). This product is identified with TLC and NMR techniques.

EXAMPLE C-2

To a solution of diphenylmethyl7α-benzamido-3-methylene-1-dethia-1-oxacepham-4α-carboxylate (94 mg) indichloromethane (4 ml) are added pyridine (32 μl) and a 0.37M solutionof phosphorus pentachloride in dichloromethane (1.08 ml) at -40° C.under nitrogen atmosphere, and the mixture is warmed up to roomtemperature, stirred for 1 hour, cooled again to -40° C., mixed withmethanol (8 ml), warmed up to 0° C., mixed with water (0.8 ml) andevaporated under reduced pressure. The residue is dissolved in ethylacetate (20 ml) and washed with water. The solution is extracted withaqueous sodium hydrogencarbonate and water. The combined aqueous extractand washing are covered with ethyl acetate, adjusted to pH 7.0 andextracted with ethyl acetate. The organic layer is separated, washedwith water, dried and evaporated to yield diphenylmethyl7α-amino-3-methylene-1-dethia-1-oxacepham-4α-carboxylate (29 mg=40%yield).

IR: ν_(max) ^(CHCl).sbsp.3 3000, 1770 sh, 1760, 1740 cm⁻¹.

D. REPLACEMENT AND TRANSFORMATION OF X AND Z

EXAMPLE D-1 ##STR43##

(1) To a solution of diphenylmethyl7α-benzamido-3ξ-hydroxy-3ξ-bromomethyl-1-dethia-1-oxacepham-4.alpha.-carboxylate(108 mg) in acetone (5 ml) containing 10% water is added potassiumcarbonate (50 mg), and the mixture is stirred at room temperature for1.5 hours, diluted with brine, and extracted with dichloromethane. Theextract is dried over magnesium sulfate and evaporated. The residue (90mg) is purified by thin-layer chromatography on silica gel plate(solvent system: benzene+ethyl acetate (2:1)) to afford diphenylmethyl7α-benzamido-3,3-epoxymethano-1-dethia-1-oxacepham-4α-carboxylate (40mg) (isomer A). Another stereoisomer B at position 3 (56 mg) is obtainedfrom the stereoisomeric starting material (140 mg).

(2) To a solution of 1-methyltetrazol-5-ylthiol (20 mg) intetrahydrofuran (2 ml) is added a 1.5M-solution of n-butyl lithium inhexane (0.05 ml), and the mixture is stirred for 30 minutes, mixed witha solution of diphenylmethyl7α-benzamido-3,3-epoxymethano-1-dethia-1-oxacepham-4α-carboxylate (56mg) (epimer B) in tetrahydrofuran (1 ml), stirred for 1 hour, mixed withaqueous sodium hydrogencarbonate, and extracted with ethyl acetate. Theextract is washed with brine, dried over magnesium sulfate, andevaporated. The residue is chromatographed on a column of silica gel (1g) deactivated with 10% water. Eluate with a mixture (9:1) of benzeneand ethyl acetate gives diphenylmethyl7α-benzamido-3-(1-methyltetrazol-5-yl)thiomethyl-3-hydroxy-1-dethia-1-oxacepham-4α-carboxylate(43 mg) (epimer B).

EXAMPLE D-2

(1) To a solution of diphenylmethyl7α-benzamido-3α-hydroxy-3β-methyl-1-dethia-1-oxacepham-4-carboxylate(100 mg) in isopropenyl acetate (5 ml) is added p-toluenesulfonicacidmonohydrate. (6mg), and the mixture is heated at 60° C. for 75minutes. After cooling, the reaction mixture is poured into icy diluteaqueous sodium hydrogencarbonate and extracted with dichloromethane. Theorganic layer is separated, washed with water, dried and evaporated togive diphenylmethyl7α-benzamido-3α-acetoxy-3β-methyl-1-dethia-1-oxacepham-4.alpha.-carboxylate(30.5% yield).

(2) The same starting material as in (1) can be treated with a mixtureof 1.1 equivalents of lithium diisopropylamide, 1.2 equivalents ofacetyl chloride, and 20 parts by volume of tetrahydrofuran at -40° C.for 45 minutes, at -20° C. for 15 minutes, and then at 0° C. for 20minutes or with 1 equivalent of pyridine and 1.2 equivalents of acetylchloride in dichloromethane to give the same product.

(3) To a solution of diphenylmethyl7β-benzamido-7α-methoxy-3α-hydroxy-3β-methyl-1-dethia-1-oxacepham-4α-carboxylate(52 mg) in dioxane (1 ml) is added trifluoroacetic acid anhydride (0.1ml) under nitrogen atmosphere under ice-cooling, and the mixture is keptat room temperature for 2 hours, mixed with water (0.3 ml), stirred for30 minutes, diluted with ice-water, and extracted with ethyl acetate.The extract is washed with water, dried, and evaporated to yield oilydiphenylmethyl7β-benzamido-7α-methoxy-3α-trifluoroacetoxy-3β-methyl-1-dethia-1-oxacepham-4α-carboxylate(64 mg).

(4) A solution of diphenylmethyl7α-benzamido-3ξ-hydroxy-3ξ-hydroxymethyl-1-dethia-1-oxacepham-4α-carboxylate(112 mg) in a mixture of pyridine (0.5 ml) and acetic anhydride (0.3 ml)is kept at 0° C. overnight. The mixture is concentrated in vacuo, pouredinto ice water, and extracted with ethyl acetate. The extract is washedwith water, dilute hydrochloric acid, aqueous sodium hydrogen carbonate,and water, dried, and concentrated to give diphenylmethyl,7α-benzamido-3ξ-hydroxy-3ξ-acetoxymethyl-1-dethia-1-oxacepham-4α-carboxylate(54 mg) as crystals melting at 118° to 120° C.

(5) To a solution of diphenylmethyl7α-benzamido-3ξ-hydroxy-3ξ-hydroxymethyl-1-dethia-1-oxacepham-4α-carboxylate(350 mg) in dichloromethane (3 ml) are added pyridine (78 μl) andmethanesulfonyl chloride (75 μl), and the mixture is stirred at 0° C.for 1 hour and at room temperature for 3 hours. The reaction mixture ispoured into ice-water, and extracted with ethyl acetate. The extract iswashed with water, aqueous sodium hydrogencarbonate, and water, dried,and evaporated to residue (370 mg) giving diphenylmethyl7α-benzamido-3ξ-hydroxy-3ξ-methanesulfonyloxymethyl-1-dethia-1-oxacepham-4α-carboxylate(145 mg) after silica gel chromatography.

REFERENCE EXAMPLES

Preparation of the starting material (1) ##STR44##

To a solution of Compound (a) (512 mg) in a mixture of benzene (10 ml)and methanol (1 ml) is added triphenylphosphine (0.4 g), and the mixturestirred at 65° C. for 1.5 hours. The residue is chromatographed on acolumn of silica gel (30 g) deactivated with 10% water. Eluate withbenzene containing 20-30% acetic acid yields 202 mg of Compound (b).

IR: ν_(max) ^(CHCl).sbsp.3 3370, 1782, 1755, 1635 cm⁻¹.

NMR: δ^(CDCl).sbsp.3 2.50-3.35m1H, 4.18s2H, 5.08s1H, 5.22s1H, 5.28d (3Hz)1H, 5.50s1H, 6.08d(3 Hz)1H, 6.93s1H, 7.20-8.00m15H.

Preparation of the starting material (2) ##STR45##

(Step 1) To a solution of diphenylmethyl2-(3-benzyl-7-oxo-2,6-diaza-4-oxabicyclo[3.2.0]hept-2-en-6-yl)-3-methyl-3-butenoate(4.6 g) in ethyl acetate (70 ml) are added 2.74M-solution ofhydrochloric acid in ethyl acetate (3.8 ml) and 1.47M-solution ofchlorine in carbon tetrachloride (12 ml), and the mixture is stirred atroom temperature for 15 minutes. Then, aqueous 5% sodium thiosulfate (80ml), sodium hydrogen-carbonate (3.4 g) and acetone (240 g) are added tothe reaction mixture, and the combined solution is kept at roomtemperature for 2.5 hours. The product is isolated by extracting withethyl acetate, drying over sodium sulfate, and evaporating to yielddiphenylmethyl2-(3-benzyl-7-oxo-2,6-diaza-4-oxabicyclo-[3.2.0]hept-2-en-6-yl)-3-chloromethyl-3-butenoate(3.33 g), mp. 82°-83° C.

(Step 2) The butenoate above is dissolved in acetone (25 ml), mixed withsodium iodide (3.3 g) and kept at room temperature for 2 hours. Thereaction mixture is concentrated to remove acetone and extracted withethyl acetate. The extract is washed with aqueous 5% sodium thiosulfateand water, dried over sodium sulfate, and evaporated to leave thecorresponding iodide (3.0 g).

(Step 3) To a solution of the iodide above (1.59 g) in a mixture ofdimethyl sulfoxide (13 ml) and water (3 ml) is added cupric oxide (0.77g), and the mixture is stirred at 39° C. for 1 hour. The reactionmixture is filtered to remove solid part and extracted with ethylacetate. The extract solution is washed with water, dried over sodiumsulfate, and evaporated to give diphenylmethyl2-(3-benzyl-7-oxo-2,6-diaza-4-oxabicyclo-[3.2.0]hept-2-en-6-yl)-3-hydroxymethyl-3-butenoate(0.35 g), mp. 40°-55° C.

    ______________________________________                                        Explanation of abbreviations in Tables                                        ______________________________________                                        Ph              = phenyl                                                      STetr           = 1-methyl-1,2,3,4-tetrazol-5-yl                              C.sub.6 H.sub.4 NO.sub.2p                                                                     = p-nitrophenyl                                               C.sub.6 H.sub.4 CH.sub.3p                                                                     = p-tolyl                                                     C.sub.6 H.sub.4 CNp                                                                           = p-cyanophenyl                                               C.sub.6 H.sub.4 Clp                                                                           = p-chlorophenyl                                              But             = tertiary butyl                                              OAc             = acetoxy                                                      between X and Z                                                                              = CH.sub.2 X and Z taken together                                             represent methylene                                           O between X and Z                                                                             = X and Z represent epoxy.                                    A               = amino or substituted amino in                                               place of R.sup.1 CONH                                         Wt              = weight of the starting material                             CH.sub.2        = weight of the starting 3-exometh-                                           ylene compound                                                EtOAc           = ethyl acetate                                               THF             = tetrahydrofuran                                             DMF             = N,Ndimethylformamide                                        c-H.sub.2 SO.sub.4                                                                            = concentrated H.sub.2 SO.sub.4                               Et.sub.2 O      = diethyl ether                                               t-BuOCl         = tertiary butyl hypochlorite                                 eq              = equivalent                                                  DBN             = 1,5-diazabicyclo[3.4.0]nonene-5                             (CH.sub.2).sub.5 NH                                                                           = piperidine                                                  Temp            =  reaction temperature                                       rt              = room temperature                                            reflux          = reflux temperature                                          hr              = hour                                                        hν           = light irradiation                                           Δ.sup.2 or Δ.sup.3 for Z                                                          = a double bond at 2(3) or 3(4)                                               present instead of leaving group at                                           position 3                                                    ______________________________________                                    

                                      TABLE I                                     __________________________________________________________________________    Cyclization                                                                    ##STR46##                                                                                            Wt  Solvent                                                                              Acid    Temp                                                                              Time                                                                             Yield                       No.                                                                              R.sup.1 B.sup.1                                                                            X   Z   (mg)                                                                              (ml)   (μl) (°C.)                                                                      (hr)                                                                             mg %  Note                  __________________________________________________________________________    1. Ph      CHPh.sub.2   50  EtOAc(2.3)                                                                           CF.sub.3 SO.sub.3 H(0.35)                                                             rt  7/4                                                                              -- >80                      2. "       "    "       50  EtOAc(2.4)                                                                           CH.sub.3 SO.sub.3 H(0.35)                                                             "   2  -- ˜10                3. "       "    "       50  THF(4) c-H.sub.2 SO.sub.4 (0.5)                                                              "   1  -- ≦70               4. "       "    "       50  C.sub.6 H.sub.6 (4)                                                                  c-H.sub.2 SO.sub.4 (0.05)                                                             "   1  -- 30                       5. "       "    "       50  CH.sub.2 Cl.sub.2 (2)                                                                SiO.sub.2 (100 mg)                                                                    "   3  -- 70                                                          HClO.sub.4 (2)                             6. "       "    "       50  CH.sub.2 Cl.sub.2 (2)                                                                Amberlyst 15                                                                          "   1  -- 60                       7. "       "    "       50  THF(2) SiO.sub.2 (100 mg)                                                                    "   15 -- 70                                                          H.sub.3 PO.sub.4 (2)                       8. "       "    "       37  CH.sub.2 Cl.sub.2 (1)                                                                BF.sub.3 Et.sub.2 O(4)                                                                "   2   13                                                                              35                       9. "       "    O       97  CH.sub.2 Cl.sub.2 (1)                                                                BF.sub.3 Et.sub.2 O(10)                                                               "   0.5                                                                               48                                                                              50                       10.                                                                              "       "    Cl  OH  293 CH.sub.2 Cl.sub.2 (4)                                                                BF.sub. 3 Et.sub.2 O(1)                                                                5  1/4                                                                              266                                                                              89 stereoisomers                                                                 mixture                  "       "    STetr.                                                                            OH  186 CH.sub.2 Cl.sub.2 (3.5)                                                              BF.sub.3 Et.sub.2 O(4)                                                                rt  2.75                                                                             175                                                                              94 stereoisomers                                     Et.sub.2 O(6.4)             mixture                  "       "    H   Br  100 CH.sub.2 Cl.sub.2 (5)                                                                BF.sub.3 Et.sub.2 O(1)                                                                "   3   84                                                                              84                          "       "    OH  OH  10880                                                                             Et.sub.2 O(300)                                                                      BF.sub.3 Et.sub.2 O(75)                                                               "   3.5                                                                               15                                                                              -- crude                                                                   (g)                            "       "    H   OH  15900                                                                             CH.sub.2 Cl.sub.2 (100)                                                              BF.sub.3 Et.sub.2 O(100)                                                              "   3  11.15                                                                            70 two stereo-                                       Et.sub.2 O(210)       (g)   isomers                                                                       isolated                 "       "    H   OH  200 CH.sub.2 Cl.sub.2 (8)                                                                CH.sub.3 C.sub.6 H.sub.4 SO.sub.3                                                     "   2  110                                                                              55 two stereo-                                              (5 mg)               isomers                                                                       isolated                 "       "    Br  OH  50  CHCl.sub.3 (4)                                                                       BF.sub.3 Et.sub.2 O(1)                                                                "   3   11                                                                              32 stereoisomer             "       "    Br  OH  88  CHCl.sub.3 (4)                                                                       BF.sub.3 Et.sub.2 O(1)                                                                "   3   24                                                                              27 "                        C.sub.6 H.sub.4 NO.sub.2p                                                             CHPh.sub.2   452 EtOAc(2.5)                                                                           BF.sub.3 Et.sub.2 O(5)                                                                rt  1  423                                                                              102                                                  CH.sub.2 Cl.sub.2 (2.5)                              C.sub.6 H.sub.4 CH.sub.3p                                                             "    "       491 EtOAc(10)                                                                            BF.sub.3 Et.sub.2 O(6.3)                                                              "   1.5                                                                              299                                                                              62                       20.                                                                              C.sub.6 H.sub.4 CNp                                                                   "    "       101 EtOAc(2)                                                                             BF.sub.3 Et.sub.2 O(1)                                                                "   3/4                                                                               47                                                                              47                          C.sub.6 H.sub.4 Clp                                                                   "    "       116 EtOAc(2)                                                                             BF.sub.3 Et.sub.2 O(1)                                                                "   1  104                                                                              90                          CH.sub.2 Ph                                                                           But  "       1371                                                                              EtOAc(16)                                                                            BF.sub.3 Et.sub.2 O(23)                                                               "   4/3                                                                              1019                                                                             74                                                   CH.sub.2 Cl.sub.2 (15)                               "       "    "       732 EtOAc(7)                                                                             BF.sub.3 Et.sub.2 O(13)                                                               "   3/4                                                                              411                                                                              56                          "       CHPh.sub.2                                                                         "       1180                                                                              CH.sub.2 Cl.sub.2 (12)                                                               CuSO.sub.4 (1.2 g)                                                                    reflux                                                                            1  1030                                                                             90                          "       CH.sub.2 Ph                                                                        "       155 EtOAc(1.8)                                                                           0.1 M BF.sub.3 Et.sub.2 O/                                                            rt  7/6                                                                               88                                                                              72                                                          EtOAc(300)                                    "       "    "       81  EtOAc(1.2)                                                                           SnCl.sub.4 (400)                                                                      "   3   25                                                                              31                          "       "    "       4030                                                                              EtOAc(50)                                                                            BF.sub.3 Et.sub.2 O(62)                                                               "   1  1880                                                                             47                          "       "    "       390 EtOAc(10)                                                                            BF.sub.3 Et.sub.2 O(3)                                                                "   3  255                                                                              65                          "       "    "       657 CH.sub.2 Cl.sub.2 (6)                                                                BF.sub.3 Et.sub.2 O(11)                                                               "   7/6                                                                              518                                                                              79                                                   EtOAc(6)                                          30.                                                                              "       CHPh.sub.2                                                                         "       4750                                                                              CH.sub.2 Cl.sub.2 (100)                                                              CuSO.sub.4 (6.48 g)                                                                   reflux                                                                            5/4                                                                              2640                                                                             56                          CH.sub.2 OPh                                                                          "    "       130 CHCl.sub.3 (2)                                                                       BF.sub.3 Et.sub.2 O(2)                                                                rt  1/4                                                                               20                                                                              15                          "       CH.sub.2 Ph                                                                        "       169 CH.sub.2 Cl.sub.2 (1.7)                                                              CuSO.sub.4 (169 mg)                                                                   40  3.5                                                                               78                                                                              46                       __________________________________________________________________________

                                      TABLE II                                    __________________________________________________________________________    Methoxylation                                                                  ##STR47##                                                                                                                              Identified                                                               after                    Wt                      Solvent   Temp.       Time                                                                              Yield                                                                            modi-                    No.                                                                              R.sup.1 B.sup.1                                                                            X  Z    (mg)                                                                             (ml)   Reagent (ml)                                                                              (°C.)                                                                      (hr)                                                                             mg % fying               __________________________________________________________________________                                                              to                  1. Ph      CH.sub.2 Ph                                                                        Cl Cl   504                                                                              CH.sub.2 Cl.sub.2 (5)                                                                0.92MCl.sub.2 /CCl.sub.                                                                   -502.49)                                                                          1/4                                                                              276                                                                              48                                                                              Z=Δ.sup.3                                                               1                                                     2NLiOCH.sub.3 (2.69)                        2. "       "    "  "    47 CH.sub.2 Cl.sub.2 (1.5)                                                              t-BuOCl(0.046)                                                                            "   1/3                                                                               46                                                                              --                                                      LiOCH.sub.3 (2 eq.)                         3. "       "    "  Δ.sup.3                                                                      93 CH.sub.2 Cl.sub.2 (10)                                                               3MBr.sub.2 (3 μl)                                                                      -25 1/3                                                                               41                                                                              42                                                      t-BuOCl(30 μl)                                                             2NLiOCH.sub.3 (0.14)                        4. "       CHPh.sub.2                                                                         "  Cl   141                                                                              CH.sub.2 Cl.sub.2 (2.1)                                                              1.1MCl.sub.2 /CCl.sub.4 (0.27)                                                            "   1/6                                                                              -- --                                                      1.3NMg(OCH.sub.3).sub.2 (0.8)               5. "       "    H  αOH                                                                          486                                                                              CH.sub.2 Cl.sub.2 (20)                                                               t-BuOCl(0.15)                                                                             -50 1/4                                                                              250                                                                              48                                                      2NLiOCH.sub.3 (1.1)                         6. "       "    "  αOAc                                                                         1310                                                                             CH.sub.2 Cl.sub.2 (54)                                                               t-BuOCl(0.4)                                                                              "   1/4                                                                              980                                                                              71                                                      2NLiOCH.sub.3 (3)                           7. "       "    Cl Cl   47 CH.sub.2 Cl.sub.2 (1.5)                                                              t-BuOCl(1.5 eq)                                                                           "   7/8                                                                              -- --                                                                              Z=Δ.sup.3                                                               7                                                     2NLiOCH.sub.3 (2 eq)                        8. "       "    "  "    300                                                                              CH.sub.2 Cl.sub.2 (5)                                                                1.1MCl.sub.2 /CCl.sub.4 (0.76)                                                            -30 1/4                                                                              124                                                                              --                                                      1.3NMg(OCH.sub.3).sub.2                                                       (1.69)                                      9. "       "    Br Br   187                                                                              CH.sub.2 Cl.sub.2 (1)                                                                t-BuOCl(0.046)                                                                            "   1  -- --                                                                              Z-Δ.sup.3,                                                              .                                                     2NLiOCH.sub.3 (0.17)    X=STetr.            10.                                                                              "       "    "  "    157                                                                              CH.sub.2 Cl.sub.2 (2.4)                                                              1.1MCl.sub.2 /CCl.sub.4 (0.4)                                                             -15 1/6                                                                              -- --                                                      1.3NMg(OCH.sub.3).sub.2 (1.1)                  "       "    H  Δ.sup.3                                                                      1360                                                                             CH.sub.2 Cl.sub.2 (30)                                                               t-BuOCl(0.51)                                                                             -30 3/4                                                                              1140                                                                             --                                                      2NLiOCH.sub.3 (2.1)                            "       "    Cl "    127                                                                              THF(7.6)                                                                             t-BuOCl(0.05)                                                                             -50 1/5                                                                               34                                                                              30                                               DMF(0.6)                                                                             2NLiOCH.sub.3 (0.23)                           "       "    "  "    272                                                                              CH.sub.2 Cl.sub.2 (5.5)                                                              t-BuOCl(0.093)                                                                            -40 1/4                                                                              300                                                                              --                                                      2NLiOCH.sub.3 (0.35)                           "       "    Br "    135                                                                                "    t-BuOCl(0.05)                                                                             -30 1  -- --                                                                              Z=Δ.sup.3,                                      2NLiOCH.sub.3 (0.2)     X=STetr.               C.sub.6 H.sub.4 Clp                                                                   CHPh.sub.2                                                                         Cl Cl   106                                                                              CH.sub.2 Cl.sub.2 (6)                                                                1.2MCl.sub.2 /CCl.sub.4 (0.35)                                                            -60 1/6                                                                              -- --                                                                              Z=Δ.sup.3,                                      2NLiOCH.sub.3 (0.55)    X=STetr.               C.sub.6 H.sub.4 CNp                                                                   "    "  "    246                                                                              CH.sub.2 Cl.sub.2 (8)                                                                1.2MCl.sub.2 /CCl.sub.4 (0.98)                                                            "   1/6                                                                              -- --                                                                              Z=Δ.sup.3,                                      2NLiOCH.sub.3 (1.57)    X=STetr.               C.sub.6 H.sub.4 NO.sub.2p                                                             "    "  "    100                                                                              CH.sub.2 Cl.sub.2 (2)                                                                1.2MCl.sub.2 /CCl.sub.4 (0.34)                                                            -50 1/6                                                                               47                                                                              42                                                                              Z=Δ.sup.3        C.sub.6 H.sub.4 CH.sub.3p                                                             "    "  "    439                                                                              CH.sub.2 Cl.sub.2 (10)                                                               1.2MCl.sub.2 /CCl.sub.4 (1.4)                                                             -55 1/6                                                                              391                                                                              79                                                                              Z=Δ.sup.3                                       2NLiOCH.sub.3 (2.3)                            CH.sub.2 Ph                                                                           But  "  "    76 CH.sub.2 Cl.sub.2 (2)                                                                1.2MCl.sub.2 /CCl.sub.4 (0.15)                                                            -50 1/6                                                                               74                                                                              --                                                                              Z=Δ.sup.3                                       2NLiOCH.sub.3 (0.34)                        20.                                                                              "       CH.sub.2 Ph                                                                        "  "    222                                                                              CH.sub.2 Cl.sub.2 (4.4)                                                              1.2MCl.sub.2 /CCl.sub.4                                                                   -7595)                                                                            1/4                                                                              193                                                                              75                                                                              Z=Δ.sup.3                                       2NLiOCH.sub.3 (1.36)                           "       CHPh.sub.2                                                                         "  "    101                                                                              CH.sub.2 Cl.sub.2 (1)                                                                0.8MCl.sub.2 /CCl.sub.4 (0.56)                                                            -50 1/6                                                                               95                                                                              83                                                                              Z=Δ.sup.3                                       2NLiOCH.sub.3 (0.52)                           "       "            78 THF(3) t-BuOCl(0.026)                                                                            -35 1/4                                                                               81                                                                              95                                               CH.sub.2 Cl.sub.2 (2)                                                                2NLiOCH.sub.3 (0.1)                            "       "    "       90 CH.sub.2 Cl.sub.2 (2)                                                                t-BuOCl(0.02)                                                                             -20 1/12                                                                              54                                                                              58                                                      2NLiOCH.sub.3 (0.09)                           ANH.sub.2                                                                             "    "       100                                                                              CH.sub.2 Cl.sub.2 (4)                                                                t-BuOCl(0.02)                                                                             -50 1/12                                                                             82 --                                                      2NLiOCH.sub.3 (0.08)                        __________________________________________________________________________

                                      TABLE III                                   __________________________________________________________________________     Addition                                                                     __________________________________________________________________________     ##STR48##                                                                                             Wt  Solvent                                          No.                                                                              R.sup.1 B.sup.1                                                                            X    Z   (mg)                                                                              (ml)   Reagent (ml)                              __________________________________________________________________________    1. Ph      CHPh.sub.2                                                                         OH   OH  100 THF (4)                                                                              KClO.sub.3 (0.2 g)                                                     H.sub.2 O (1)                                                                        OsO.sub.4 (0.02 g)                        2. "       "    SCH.sub.3                                                                          Cl  100 AcOEt (3)                                                                            0.5MCH.sub.3 SCl/CCl.sub.4 (0.6)          3. "       "    Cl   "   519 CH.sub.2 Cl.sub.2 (10)                                                               0.76NCl.sub.2 /CCl.sub.4 (1.6)            4. "       "    "    "   103 CH.sub.2 Cl.sub.2 (1)                                                                0.75MCl.sub.2 /CCl.sub.4 (0.3)            5. "       CH.sub.2 Ph                                                                        "    "   141 CH.sub.2 Cl.sub.2 (3)                                                                0.75MCl.sub.2 /CH.sub.2 Cl.sub.2                                              (1.4 eq)                                  6. "       H    Br   Br   60 CH.sub.2 Cl.sub.2 (3)                                                                0.84MBr.sub.2 /CCl.sub.4                                                      (0.75)                                    7. "       CHPh.sub.2                                                                         "    "   162 CH.sub.2 Cl.sub.2 (0.5)                                                              Br.sub.2 (0.02)                           8. C.sub.6 H.sub.4 CH.sub.3p                                                             "    Cl   Cl  439 CH.sub.2 Cl.sub.2 (10)                                                               1.2MCl.sub.2 /CCl.sub.4 (2.4)             9. C.sub.6 H.sub.4 Clp                                                                   "    "    "   106 CH.sub.2 Cl.sub.2 (6)                                                                1.2MCl.sub.2 /CCl.sub.4 (0.5)             10.                                                                              C.sub.6 H.sub.4 CNp                                                                   "    "    "   246 CH.sub.2 Cl.sub.2 (8)                                                                1.2MCl.sub.2 /CCl.sub.4 (1.5)                C.sub.6 H.sub.4 NO.sub.2p                                                             "    "    "   100 CH.sub.2 Cl.sub.2 (2)                                                                1.2MCl.sub.2 /CCl.sub.4 (0.52)               CH.sub.2 Ph                                                                           But  "    "   100 CH.sub.2 Cl.sub.2 (2)                                                                1.2MCl.sub.2 /CCl.sub.4 (0.7)                "       CH.sub.2 Ph                                                                        "    "   222 CH.sub.2 Cl.sub.2 (4.4)                                                              1.2MCl.sub.2 /CCl.sub.4 (1.5)                "       CHPh.sub.2                                                                         "    "   2960                                                                              CH.sub.2 Cl.sub.2 (30)                                                               1.36MCl.sub.2 /CCl.sub.4 (8.1)               "       "    "    "   705 CH.sub.2 Cl.sub.2 (7)                                                                Cl.sub.2 (1.77 eq)                           CH.sub.2 OPh                                                                          "    "    "    68 CH.sub.2 Cl.sub.2 (1.4)                                                              1.5MCl.sub.2 /CCl.sub.4                                                       (1.3 eq)                                  __________________________________________________________________________                             Temp                                                                              Time Yield   Identified after                                          No.                                                                              (°C.)                                                                      (hr) mg  %   modifying to                        __________________________________________________________________________                          1.  70 2.5  112 --                                                            2. rt  1    132 --                                                            3. -20 2/3 hν                                                                          484  86                                                           4. "   1/2 hν                                                                          120 --                                                            5. -50 1/2 hν                                                                          170 >100                                                          6. -20 to                                                                            5     66 --                                                               +10                                                                        7. -30 1.5  187 --                                                            8. -50 1/6 hν                                                                          --  >80 Z = Δ.sup.3                                         9. "   1/4 hν                                                                          --  >80 "                                                         10.                                                                              "   7/60 hν                                                                         --  >80 "                                                         11.                                                                              "   1/3 hν                                                                          --   42                                                           12.                                                                              -55 2/15 hν                                                                          76  64                                                           13.                                                                              -54 1/6 hν                                                                          --  >65 Z = Δ.sup.3                                         14.                                                                              -30 1/4 hν                                                                          2420                                                                               76 "                                                         15.                                                                              -25 --   --  >80 "                                                         16.                                                                              -50 1/2 hν                                                                           39  54 "                                   __________________________________________________________________________

    TABLE IV      Elimination (1)      ##STR49##       Wt Solvent  Temp Time Yield  No. R.sup.1 B.sup.1 X Z E (mg) (ml)     Reagent (μl) (°C.) (hr) mg % Note       1. Ph H H OH αOCH.sub.3 206 CH.sub.2 Cl.sub.2 (5) CH.sub.3     SO.sub.2 Cl 0 1 -- --          C.sub.5 H.sub.5 N 2. " CH.sub. 2 Ph  Cl     αOH βH 1000 THF (20) SOCl.sub.2 (905) rt 63 688 71     C.sub.5 H.sub.5 N (825) 3. " " " βOH " 200 CH.sub.2 Cl.sub.2 (4)     SOCl.sub.2 (163) " 2.5 100 --         C.sub.5 H.sub.5 N (182) 4. " " "     Cl " 50 CH.sub.2 Cl.sub.2 (2) 2NLiOCH.sub.3 /CH.sub.3 OH -50 1/3 45 97           (0.2 ml) 5. " " Br Br " 300 CH.sub.2 Cl.sub.2 (5) DBN (97) rt 1/3     272 76       (CH.sub.2) 6. " " STetr OH " 144 CH.sub.2 Cl.sub.2 (2.2)     SOCl.sub.2 (60) 0 3/4 98 --         C.sub.5 H.sub.5 N (133) rt 1 7. " "     " Br " 452 CH.sub.2 Cl.sub.2 (10) (CH.sub.2).sub.5 NH (1060) 0 3 234 48     8. " CHPh.sub.2 H βOH " 200 CH.sub.2 Cl.sub.2 (10) t-BuCONCO (131)     rt 5 88 46           (days) 9. " " " αOH " 1929 CH.sub.2 Cl.sub.2     (10) SOCl.sub.2 (433) " 3/4 627 34         C.sub.5 H.sub.5 N (1050) 10.     " " " βOH " 97 CH.sub.2 Cl.sub.2 (2) SOCl.sub.2 (29) " 4.5 91 --         DMF (0.001) C.sub.5 H.sub.5 N (65) 11. " " " " " 973 CH.sub.2     Cl.sub.2 (20) POCl.sub.3 (367) " 40 296 --         C.sub.5 H.sub.5 N     (971) 12. " " " OH " 15000 CH.sub.2 Cl.sub.2 (100) SOCl.sub.2 (3000) 0     5/4 2650 25 Z = Δ.sup.3         C.sub.5 H.sub.5 N (6800) rt 9/4     1050 11 Z = Δ.sup.2 13. " " " OCOCF.sub.3 αOCH.sub.3 103     C.sub.5 H.sub.5 N (1) (CF.sub.3 CO).sub.2 O (300) rt 2/3 121 --       (X     = OH) 14. " " Cl OH βH 483 CH.sub.2 Cl.sub.2 (5) SOCl.sub.2 (300) "     2.5 252 52         α     CH.sub.3 C.sub.5 H.sub.4 N (800) 15. " " " Cl " 519 CH.sub.2 Cl.sub.2     (5) DBN (140) -20 10 484 86       (CH.sub.2) 16. " " " " αOCH.sub.3      300 CH.sub.2 Cl.sub.2 (6) 2NLiOCH.sub.3 /CH.sub.3 OH -50 1/6 193 69         (1.2 ml) 17. " " " " " 141 CH.sub.2 Cl.sub.2 (2) 2NLiOCH.sub.3     /CH.sub.3 OH -25 1/6 119 78         (0.2 ml) 18. " " Br Br βH 157     CH.sub.2 Cl.sub.2 (0.5) DBN (20) -20 1/2 135 76       (CH.sub.2) 19. " "     " " " 142 (CH.sub.3).sub.2 CO (1.5) NaSTetr (90) rt 15 115 -- X = STetr     in       (CH.sub.2)       the product 20. " " STetr OH " 182 CH.sub.2     Cl.sub.2 (5) SOCl.sub.2 (300) " 2.5 175 --         C.sub.5 H.sub.5 N     (600) 21. C.sub.6 H.sub.4 CH.sub.3p " " Cl αOCH.sub.3 150 CH.sub.2     Cl.sub.2 (2) (CH.sub.2).sub.5 NH (40) 0 1/3 102 72 22.  C.sub.6 H.sub.4     NO.sub.2p " " " " 72 CH.sub.2 Cl.sub.2 (2) (CH.sub.2).sub.5 NH (20) "     1/3 55 81 23. C.sub.6 H.sub.4 CNp " " " " 83 CH.sub.2 Cl.sub.2 (2)     (CH.sub.2).sub.5 NH (15) " 1/3 64 82 24. C.sub.6 H.sub.4 Clp " " " " 96     CH.sub.2 Cl.sub.2 (6) 2NLiOCH.sub.3 /CH.sub.3 OH -50 1/3 78 87     (0.5 ml) 25. CH.sub.2 Ph CH.sub.2 Ph Cl " βH 205 CH.sub.2 Cl.sub.2     (4) (CH.sub.2).sub.5 NH (80) 0 2.5 145 65       (CH.sub.2) 26. " " STetr     " αOCH.sub.3 215 CH.sub.2 Cl.sub.2 (4) 2NLiOCH.sub.3 /CH.sub.3 OH     -50 1/4 160 70         (0.9 ml) 27. " CHPh.sub.2 Cl " " 210 CH.sub.2     Cl.sub.2 (5) (CH.sub.2).sub.5 NH  10 1/2 104 53 28. " " " " βH 2960     CH.sub.2 Cl.sub.2 (30) (CH.sub.2).sub.5 NH (660) -10 1 2420 76     (CH.sub.2) 29. " " " " " 705 CH.sub.2 Cl.sub.2 (7) (CH.sub.2).sub.5 NH     (160) -15 2/3 586 78       (CH.sub.2) 30. " " STetr " αOCH.sub.3     123 CH.sub.2 Cl.sub.2 (6) 2NLiOCH.sub.3 /CH.sub.3 OH -50 1/6 87 67       (0.6 ml) 31. CH.sub.2 OPh CH.sub.2 Ph Cl " βH 68 CH.sub.2     Cl.sub.2 (1.4) (CH.sub.2).sub.5 NH (16) 0 0.5 39 54       (CH.sub.2)     32.      ##STR50##      CHPh.sub.2 " " αOCH.sub.3 60 CH.sub.2 Cl.sub.2 (2) 2NNaOCH.sub.3     /CH.sub.3 OH(0.2) -50 1/3 51 81  33. Ph Si(CH.sub.3).sub.3 " " βH     44 THF (1) DBN (18 mg) NaSTetr rt 3.5 18 44 X = STetr in         (28     mg)/THF (500)     the product

                                      TABLE V                                     __________________________________________________________________________     Continuous process                                                           __________________________________________________________________________     ##STR51##                                                                     ##STR52##                                                                                    wt CH.sub.2 Cl.sub.2                                                                  Cl.sub.2 /CCl.sub.4                                                                Temp                                                                              Time                                                                              2NLiOCH.sub.3 /                          No.                                                                              R.sup.1 B.sup.1                                                                            (mg)                                                                             (ml) (M:ml)                                                                             (°C.)                                                                      (min)                                                                             CH.sub.3 OH(μl)                       __________________________________________________________________________    1. CH.sub.2 Ph                                                                           CH.sub.2 Ph                                                                        222                                                                              4.4  1.22;                                                                              -54 10 (hν )                                                                       1360                                                             1.43                                                  2. Ph      CHPh.sub.2                                                                         504                                                                              5    0.92;                                                                                0  90 2690                                                             3.74                                                  3. CH.sub.2 Ph                                                                           "    101                                                                              1    0.8; -25 120  520                                                             0.837                                                 4. C.sub.6 H.sub.4 NO.sub.2p                                                             "    100                                                                              2    1.2; -50 20 (hν)                                                                         483                                                             0.515                                                 5. C.sub.6 H.sub.4 CH.sub.3p                                                             "    439                                                                              10   1.2; "   10 (hν)                                                                        2300                                                             2.4                                                   6. C.sub.6 H.sub.4 CNp                                                                   "    246                                                                              8    1.2  "    7 (hν)                                                                        1570                                                             1.47                                                  7. C.sub.6 H.sub.4 Clp                                                                   "    106                                                                              6    1.2  "   15 (hν)                                                                         550                                                             0.53                                                  __________________________________________________________________________                          Temp                                                                              Time                                                                              Yield                                                              No.                                                                              (°C.)                                                                      (min)                                                                             mg % Note                                       __________________________________________________________________________                       1. -75 10  193                                                                              75                                                                              partial CH.sub.3ester                                                         exchange                                                      2. -50 "   276                                                                              48                                                              3. "   "    95                                                                              83                                                              4. "   "    47                                                                              42                                                              5. "    5  391                                                                              79                                                              6. "   10  251                                                                              --                                                                              identified as                                                                 3-CH.sub.2 STetr                                              7. "   "    65                                                                              --                                                                              identified as                                                                 3-CH.sub.2 STetr                           __________________________________________________________________________

                                      TABLE VI                                    __________________________________________________________________________     (1) Physical constants of                                                    __________________________________________________________________________     ##STR53##                                                                    No.                                                                              R.sup.1                                                                          B.sup.1                                                                            X    Z      mp. (°C.)                                                                   IR: ν .sub.max.sup.CHCl.sbsp.3                 __________________________________________________________________________                                cm.sup.-1                                         1  Ph H                --   3350, 1670, 1660,                                                             1600, 1580                                        2  "  "    Cl   Cl     118-122                                                                            3330, 1778, 1768,                                                             1647, 1605, 1578,                                                             1530.                                             3  "  "    Br   Br     --   --                                                4  "  "    H    Δ.sup.2                                                                        --   3000, 1775, 1725,                                                             1660.                                             5  "  "    H    Δ.sup.3                                                                        --   --                                                6  "  CH.sub.2 Ph                                                                        Cl   Cl     --   3430, 1781, 1736,                                                             1670.                                             7  "  "    Br   Br     --   --                                                8  "  "    H    Δ.sup.3                                                                        208-212                                                                            3440, 1785, 1720,                                                             1665.                                             9  "  "    Cl   "      186-188                                                                            3250, 1771, 1729,                                                             1643 (Nujol).                                     10 "  "    Br   "      165-169                                                                            3275, 1780, 1742,                                                             1647.                                             11 "  "    STetr                                                                              "      186-189                                                                            3430, 1791, 1724,                                                             1675, 1634, 1584.                                 12 "  CHPh.sub.2                                                                         H    OH     --   3385br, 1775br,                                                               1740br, 1648br,                                                               (Nujol).                                          13 "  "    "    "      207-209                                                                            3530, 3320, 1783,                                                             1753, 1745, 1723,                                                             1638 (Nujol)                                      14 "  "    "    αOCOCH.sub.3                                                                   --   3430, 1780, 1745,                                                             1660.                                             15 "  "    "    Br      --  3450, 1793, 1749,                                                             1673.                                             16 "  "                --   1777, 1745, 1666.                                 17 "  "    O           --   1780, 1740, 1675.                                 18 "  "    "    "      --   1780, 1745, 1680.                                 __________________________________________________________________________    No.     NMR: δ .sub.ppm.sup.CDCl.sbsp.3 (Hz values show coupling                constants)                                                            __________________________________________________________________________    1       4.36s2H, 5.1s2H, 5.33brs3H, 7.4- 8.0m5H(CDCl.sub.3 + CD.sub.3                 OH)                                                                   2       4.08s2H, 4.65s1H, 5.00d(8Hz)1H, 5.37s1H, 7.3-8.2m5H,                          9.37d(8Hz)1H.                                                         3       (3.83d + 4.33d)ABq(13Hz)2H, (3.9d + 4.2d)ABq(10Hz)2H,                         4.8s1H, 5.15s1H, 5.35s1H, 7.2-8.1m5H(CD.sub.3 COCD.sub.3).            4       1.62d(1Hz)3H, 4.51brs1H, 4.97d(8Hz)1H, 5.33s1H,                               6.24brs1H, 7.14-8.07m5H.                                              5           --                                                                6       3.52d + 3.80d(12Hz)ABq2H, (3.93d + 4.28d(12Hz)ABq2H,                          4.85s1H, 5.01d(7Hz)1H, 5.20s2H, 5.41s1H, 7-8m11H.                     7       not separated                                                         8       2.00s3H, 4.37s2H, 5.03s1H, 5.10d(8Hz)1H, 5.35s2H,                             7.2-8.0m10H.                                                          9       4.56s2H, 4.60s2H, 4.93dd(8;1Hz)1H, 5.33d(1Hz)1H, 5.36s                        2H, 8.1-7.2m10H, 9.42dd(8;1Hz)1H(CD.sub.3 SOCD.sub.3).                10      4.48s2H, 4.63s2H, 4.97dd(8;1Hz)1H, 5.32d(1Hz)1H, 5.38s                        2H, 7.3-8.0m10H, 9.40d(8Hz)1H (CD.sub.3 SOCD.sub.3).                  11      3.81s3H, 4.20ABq(13Hz)2H, 4.55s2H, 4.93d1H, 5.05s1H,                          5.27s2H, 7.22-7.6m9H, 7.7-7.85m2H.                                    12      1.40s3H, 3.42d(11.5Hz)1H, 3.85d(11.5Hz)1H, 4.35s1H,                           4.75d(8Hz)1H, 5.27s1H, 5.67s1H, 6.77s1H, 9.08d(8Hz)                           1H, 7.1-7.5m, 7.7-7.9m15H.                                            13      0.83s3H, 3.47s1H, 3.73s1H, 4.30s1H, 4.88d(8Hz)1H, 5.25s                       1H, 5.62s1H, 6.80s1H, 7.1-7.6, 7.7-7.9m15H, 9.07d(8Hz)                        1H.                                                                   14      1.43s3H, 1.77s3H, (3.45d + 4.20d)ABq(11Hz)2H, 5.03d(8Hz)                      1H, 5.20s1H, 5.43s1H, 6.93d(8Hz)1H, 7.00s1H, 7.2-7.9m15H.             15      1.95s3H, (3.82d + 4.52d)ABq(11Hz)2H, 4.77s1H, 5.05d(8Hz)                      1H, 5.47s1H, 6.93s1H, 7.1-7.9m15H.                                    16      4.27s2H, 5.05d(8Hz)1H, 5.23s1H, 5.3752H, 5.42s1H, 0.95s                       1H, 7.12d(8Hz)1H, 7.2-7.9m15H.                                        17      2.72 + 3.06ABq(4Hz)2H, (3.40 + 4.10)ABq(12Hz)2H, 4.30s1H,                     5.05d(7Hz)1H, 5.40s1H, 6.95s1H, 7.1-7.5m13H, 7.7-7.9m2H.              18      (2.88 + 3.98)ABq(6Hz)2H, 3.40 + 4.15)ABq(12Hz)2H, 4.55s1H,                    5.18d(8Hz)1H, 5.45s1H, 6.98s1H, 7.3-7.4m13H, 7.7-7.9m12H.             __________________________________________________________________________

                                      TABLE VI (2)                                __________________________________________________________________________     ##STR54##                                                                                              mp.                                                                              IR:                                              No.                                                                              R.sup.1 B.sup.1                                                                            X     Z   (°C.)                                                                     ν .sub.max.sup.CHCl.sub.3                                                          NMR: γ .sub.ppm.sup.CDCl.sub.3                                          Hz values show coupling                  __________________________________________________________________________                                         constants)                               19 Ph      CHPh.sub.2                                                                         OH    OH  -- --      (3.11d + 3.45d)ABq(12Hz)2H, 3.83s2H,                                          4.66s1H,                                                                      5.1d(7Hz)1H, 5.4s1H, 5.9s1H,                                                  7.1-8.0m15H                                                                   (CDCl.sub.3CD.sub.3 OD).                 20 "       "    OAc   OH  118-                                                                             3200,1760,1740,                                                                       1.8s3H, 3.86brs4H, 4.53s1H,                                                   5.01d(8Hz)1H, 5.36s1H,                                             120                                                                              1635(Nujol).                                                                          6.06s1H, 6.9s1H, 7.2-8.1m15H.            21 "       "    O.sub.3 SCH.sub.3                                                                     " --   --    2.75s3H, 3.83br4H, 4.75s1H,                                                   5.06d(7Hz)1H, 5.36s1H,                                                        6.88s1H, 7-8m15H.                        22 "       "    H     Δ.sup.3                                                                     144-                                                                             3440,1782,1722,                                                                       1.92s3H, 4.23s2H, 4.90s1H,                                                    5.07d(8Hz)1H, 6.88s1H,                                             146                                                                              1663.   7.1- 8.0m16H.                            23 "       "    Cl    OH  -- 3550br, 3.87s2H, 3.98s2H, 4.93s1H,                                                    4.97d(8Hz)1H, 5.40s1H,                                                3450-3200,                                                                            6.97s1H, 7.23-7.6m13H, 7.7-7.9m2H.                                    1782,1745,1670.                                  24 "       "     "     "  -- 3550,3450-3200,                                                                       (3.08 + 3.38)ABq(12Hz)2H, 3.83brs2H,                                          4.78s1H,                                                              1780,1740,1665.                                                                       5.10d(7Hz)1H, 5.45s1H, 6.93s1H,                                               7.25-7.58m13H,                                                                7.7-7.9m2H.                              25 "       "    Cl    Cl  --   --    (3.37 + 3.69d)(12Hz)ABq2H, (3.88d +                                           4.23d(12Hz)2H,                                                                5.00s1H, 5.08d(7Hz)1H, 5.38s1H,                                               6.93s1H,                                                                      7.02d(7Hz)H, 7-8m15H.                    26 "       "    SCH.sub.3                                                                            "  --   --    2.0s3H, (3.01d + 3.36d)ABq(12Hz)2H,                                           (3.65d +                                                                      3.95d)ABq2H, 4.37s1H, 4.8d1H,                                                 5.18s1H, 6.57s1H,                                                             6.8-7.6m15H.                             27 "       "    Stetr OH  -- 3350br,1777,                                                                          TLC: Rf = 0.57 & 0.63 (for each                                               isomer at 3)                                                          1745,1669.                                                                            (SiO.sub.2 /PhH + EtOAc(1:1).            28 "       "    Cl    Δ.sup.3                                                                     120-                                                                             3375,1790,1728,                                                                       4.35s2H, 4.48s2H, 4.98s1H,                                                    5.02d(6Hz)1H, 6.90s1H,                                             128                                                                              1670.   7.1-8.0m16H.                             29 "       "    STetr  "  203-                                                                             3450,1792,1725,                                                                       3.77s3H, 4.20s2H, 4.57s2H,                                                    4.90d(7Hz)1H, 5.07s1H,                                             205                                                                              1680.   6.93s1H 7.2-7.9m16H.                     30 "       "    Br    OH  -- 3600-3150,1780,                                                                       (2.93 + 3.28)ABq(11Hz)2H, 4.57brs2H,                                          4.82s1H,                                                              1740,1670.                                                                            5.12d(7Hz)1H, 5.43s1H, 6.97s1H,                                               7.2-7.6m13H,                                                                  7.7-8.2m2H.                              31 "       "     "     "  -- 3550,3440-3150,                                                                       3.78s2H, 3.97s2H, 5.02s1H,                                                    5.02d(7Hz)1H, 5.40s1H,                                                1780,1745,1675.                                                                       7.03s1H, 7.3-7.5m13H, 7.8-7.9m2H.        32 "       "     "    Br  -- 3450,1788,1740,                                                                       (3.30d + 3.60d)(12Hz)ABq2H, (3.87d +                                          4.13d)ABq                                                             1673.   (12Hz)2H, 5.0d(8Hz)1H, 5.07s1H,                                               5.37s1H, 6.87s1H,                                                             7.1-7.9m16H.                             33 "       "     "    Δ.sup.3                                                                     -- 3400,1790,1727,                                                                       (4.10d + 4.27d)ABq(7Hz)2H,                                                    4.63brs2H, 5.00s1H,                                                   1668.   5.00d(7Hz)1H, 6.90s1H, 7.2-7.9m16H.      34 C.sub.6 H.sub.4 CH.sub.3 p                                                            "              187-                                                                             1775,1743,1668.                                                                       2.36s3H, 4.20s2H, 4.90-5.43m5H,                                               6.83s1H,                                                           188        7.0-7.9m14H.                             35 C.sub.6 H.sub.4 Clp                                                                   -     "     "  192-                                                                             3430,1777,1745,                                                                       4.23s2H, 4.97d(8Hz)1H, 5.17s1H,                                               5.3-5.4m3H, 6.85s1H,                                               193                                                                              1672,1599.                                                                            7.2-7.5m12H, 7.73d(8Hz)1H.               36 C.sub.6 H.sub.4 CNp                                                                   "     "     "  148-                                                                             3435,2235,1775,                                                                       4.23s2H, 4.97d(8Hz)1H, 5.17s1H,                                               5.3-5.4m3H, 6.87s1H,                                               149                                                                              1745,1675,1615.                                                                       7.3-7.5m10H, (7.67d                                                           + 7.90d)ABq(8Hz)4H.                      37 C.sub.6 H.sub.4 NO.sub.2 p                                                            "     "     "  -- 1772,1741,1679.                                                                       4.23s2H, 4.90-5.50m5H, 6.85s1H,                                               7.16-8.36 m14H.                          38 CH.sub.2 OPh                                                                          "     "     "  -- 3415,1780,1745,                                                                       4.33brs2H, 4.60s2H, 5.03d(8Hz)1H,                                             5.30s1H, 5.38s2H,                                                     1695.   5.47s1H, 7.00s1H, 7.22d(8Hz)1H,                                               6.9-7.8m15H.                             __________________________________________________________________________

                                      TABLE VI (3)                                __________________________________________________________________________     ##STR55##                                                                    No.  R.sup.1                                                                             B.sup.1                                                                            X  Z  mp. (°C.)                                                                   IR: ν .sub.max.sup.CHCl.sbsp.3                                                      NMR: δ .sub.ppm.sup.CDCl.sbsp.3                                         Hz value shows a coupling                 __________________________________________________________________________                                        constant)                                 39   CH.sub.2 OPh                                                                        CH.sub.2 Ph                                                                        Cl Δ.sup.3                                                                    162-164                                                                            3420,1796,1725,                                                                        4.48s2H, 4.56s4H, 4.90d(8Hz)1H,                                               5.10s1H, 7.03s1H, 6.6-                                               1695.    7.7m16H.                                  40   "     CHPh.sub.2 --   3410,1777,1742,                                                                        4,22s2H, 4.50s2H, 4.93d(8Hz)1H,                                               5.18s1H, 5.26s2H,                                                    1691.    5.33s1H, 6.05s1H, 7.5-6.6m16H.            41   "     "    Cl Δ.sup.3                                                                    162-164                                                                            3420,1794,1725,                                                                        4.48s2H, 4.56s4H, 4.90d(8Hz)1H,                                               5.10s1H, 7.03s1H,                                                    1695.    7.7-6.7m16H.                              42   CH.sub.2 Ph                                                                         t-Bu       138-139                                                                            2982,1773,1732,                                                                        1.41s9H, 3.56s2H, 4.26s2H,                                                    4.73d(8Hz)1H, 4.88s1H,                                               1680.    5.06-5.3m3H, 6.58d(8Hz)1H, 7.26s5H.       43   "     "    Cl Cl      1788,1731,1683.                                                                        L.50s9H, 3.60s2H, 3.73d(4Hz)2H,                                               (3.90d +                                                                      4.30d)ABq(12Hz)2H, 4.66s1H,                                                   4.76d(4Hz)1H, 7.30s5H.                    44   "     CH.sub.2 Ph                                                                              127-131                                                                            3425,1776,1742,                                                                        3.60s2H, 4.27s2H, 4.77d(8Hz)1H,                                               5.08s1H, 5.18-5.28m5H,                                               1681.    6.37d(8Hz)1H, 12-7.5m10H.                 45   "     "    Cl Δ.sup.3                                                                    137-140                                                                            3265,1780,1736,                                                                        3.45s2H, 4.45s2H, 4.51s2H,                                                    4.83d(8Hz)1H, 4.95s1H,                                               1660(Nujol).                                                                           5.31s2H, 7.2-7.7m10H(CD.sub.3                                                 SOCD.sub.3.CDCl.sub.3).                   46   "     CHPh.sub.2 110-112                                                                            3425,1777,1745,                                                                        3.51s2H, 4.15s2H, 4.73d(7.5Hz)1H,                                    1684,1604.                                                                             5.12s2H, 5.25d(4Hz)2H,                                                        6.40d(7.5Hz)1H,                                                               6.82s1H, 7.07- 7.5m15H.                   47   "     "    Cl Cl --     --     TLC: Rf = 0.53(SiO.sub.2 /C.sub.6                                             H.sub.6 + CH.sub.3 COOC.sub.2                                                 H.sub.5)                                  48   "     "     " Δ.sup.3                                                                    180-183                                                                            3295,1788,1733,                                                                        3.57s2H, 4.4-4.6m4H, 4.73d(8Hz)1H,                                            5.07s1H, 6.90s1H,                                                    1658,1536(Nujol)                                                                       7.0-8.0m15H, 8.75d(8Hz)1H(CD.sub.3                                            SOCD.sub.3 + CD.sub.3 OD).                49   7-amino                                                                             "          --   3000,1770,1760,                                                                        1.72brs2H, 4.23s2H, 5.03s1H, 5.15s1H,                                         5.2-5.4m2H,                                    deriv.                1740.    6.87s1H, 7.2-7.5m10H.                     __________________________________________________________________________

                                      TABLE VI (4)                                __________________________________________________________________________     ##STR56##                                                                                                mp.                                               No.                                                                              R.sup.1 B.sup.1                                                                            X    Z      (°C.)                                                                     IR: ν .sub.max.sup.CHCl.sub.3                                                      NMR: γ.sup.CDCl.sbsp.3 (Hz                                              values show coupling                   __________________________________________________________________________                                           constants)                             1  Ph      H    H    αOH                                                                            100-                                                                             3330,1765,1662                                                                        1.50s3H, 3.52s3H, (3.53d +                                                    3.93d)ABq2H,                                                       105                                                                              (KBr).  4.33s1H, 5.33s1H, 7.4-8.2m5H,                                                 (CD.sub.3 COCD.sub.3)                  2  "       "    "    βOAc                                                                            203-                                                                             3280,1785,1739,                                                                       1.50s3H, 1.98s3H, 3.55s3H,                                                    5.00s1H, 5.60s1H,                                                  213                                                                              1722,1659(KBr)                                                                        7.4-8.1m5H (CDCl.sub.3 + CD.sub.3                                             OD = 4:1)                              3  "       "    "    βOCOCF.sub.3                                                                    108-                                                                             1780,1740,1660                                                                        --                                                                 113                                                                              (KBr)                                          4  "       CH.sub.2 Ph                                                                        Cl   Cl     --   --    --                                     5  "       "    Br   Br     --   --    --                                     6  "       "    STetr.                                                                             Δ.sup.3                                                                        -- 3420,2840,1790,                                                                       3.59s3H, 3.83s3H, 4.27s2H,                                                    4.60s2H, 5.15s1H,                                                     1725,1680.                                                                            5.32s2H, 7.00-7.92m11H                 7  "       CHPh.sub.2       196-                                                                             3425,1780,1746,                                                                       3.53s3H, 4.23s2H, 5.17 + 5.27-3H,                                             5.47s1H,                                                           198                                                                              1683    6.87s1H, 7.2-8.0m17H.                  8  "       "    H    αOH                                                                            -- 3430,3350,1780,                                                                       1.43s3H, 3.52s3H, (3.53d +                                                    3.83d)(12Hz)ABq2H,                                                    1747,1690.                                                                            4.57s1H, 5.40s1H, 3.03brs1H,                                                  6.9-8.0m17H.                           9  "       "    "    βOAc                                                                            -- 3430,1782,1740,                                                                       1.27s3H, 1.97s3H, 3.60s3H, (3.88d                                             + 4.32d)                                                              1690.   (12Hz)2H, 5.22brs1H, 5.60s1H,                                                 7.0-8.1m16H.                           10 "       "    "    βOCOCF.sub.3                                                                    --   --    1.50s3H, 2.67brs1H, 3.58s3H,                                                  3.82s2H, 4.55s1H,                                                             5.42s1H, 6.9-8.2m16H.                  11 "       "    "    Δ.sup.3                                                                        -- 3430,1788,1728,                                                                       1.95s3H, 3.63s3H, 4.25s2H,                                                    5.12s1H, 6.96s1H,                                                     1688.   7.2-8.1m15H.                           12 "       "    Cl   Cl     -- 3430,1785,1748,                                                                       (3.40d + 3.70d)ABq(12Hz)2H,                                                   3.57s3H, (3.88d +                                                     1684.   4.30d)ABq (12Hz)2H, 5.02s1H,                                                  5.43s1H, 6.93s1H, 7.2-8.2m.            13 "       "    "    Δ.sup.3                                                                        -- 3430,1787,1728,                                                                       3.63s3H, 4.50s2H, 4.55s2H,                                                    5.25s1H, 7.00s1H,                                                     1682.   7.1-7.95m16H.                          14 "       "    Br   Br     -- 3430,1789,1740,                                                                       3.50ABq(19;12Hz)2H, 3.53s3H,                                                  4.08ABq                                                               1688,1605,1585.                                                                       (19;12Hz)2H, 5.07s1H, 5.37s1H,                                                6.90s1H,                                                                      7.2-8.0m16H,                           15 p-CH.sub.3 C.sub.6 H.sub.4                                                            "    Cl   Δ.sup.3                                                                        -- 1788,1727,1680.                                                                       2.38s3H, 3.60s3H, 4.45s2H,                                                    4.50s2H, 5.20s1H,                                                             6.93s1H, 7.06-7.96m14H.                16 "       "    STetr.                                                                             "      -- 1788,1720,1683.                                                                       2.38s3H, 3.60s3H, 3.76s3H,                                                    4.26s2H, 4.61s2H,                                                             5.16s1H, 6.91s1H, 6.96s1H,                                                    7.10-7.90m14H.                         17 NO.sub.2 C.sub.6 H.sub.4                                                              CHPh.sub.2                                                                         Cl   Δ.sup.3                                                                        -- 1788,1728,1690.                                                                       3.61s3H, 4.45s2H, 4.55s2H,                                                    5.21s1H, 6.93s1H,                                                             7.06-8.36m14H.                         18 "       "    STetr.                                                                             "      -- 1790,1725,1695.                                                                       3.65s3H, 3.80s3H, 4.25s2H,                                                    4.66s2H, 5.16s1H,                                                             6.88s1H, 7.13-8.36m14H.                19 ClC.sub.6 H.sub.4                                                                     "    "    "      --   --    3.60s3H, 3.77s3H, 4.25s2H,                                                    4.63s2H, 5.15s1H,                                                             6.92s1H, 8m14H.                        20 NCC.sub.6 H.sub.4                                                                     "    "    "      -- 3425,2230,1790,                                                                       3.63s3H, 3.73s3H, 4.25s2H,                                                    5.17brs2H, 5.17s1H,                                                   1721,1693,1632.                                                                       6.92s1H, 7.2-8.3m14H.                  __________________________________________________________________________

                                      TABLE VI (5)                                __________________________________________________________________________     ##STR57##                                                                                               mp.                                                No.                                                                              R.sup.1                                                                              B.sup.1  X    Z  (°C.)                                                                     IR: ν .sub.max.sup.CHCl.sbsp.3                                                      NMR: δ.sup.CDCl.sbsp.3 (Hz                                              values show coupling                   __________________________________________________________________________                                           constants)                             21 PhCH.sub.2                                                                           CH.sub.3 Cl   "  -- 3410,1285,1795,                                                                        3.43s3H, 3.65s2H, 3.87s3H,                                                    4.50s4H, 5.07s1H,                                                    1727,1696.                                                                             6.47brs1H, 7.33brs5H.                  22 "      Bu-t     "    "  --   --     1.50s9H, 3.43s3H, 3.66s2H,                                                    4.46s4H, 5.05s1H,                                                             6.66s1H, 7.30s5H.                      23 "      "        STetr.                                                                             "  -- 3400,1783,1700.                                                                        1.55s9H, 3.43s3H, 3.66s2H,                                                    3.93s3H, 4.30s2H,                                                             4.56s2H, 5.01s1H, 6.41s1H,                                                    7.30s5H.                               24 "      CH.sub.2 Ph                                                                            Cl   "  -- 3410,1788,1725,                                                                        3.38s3H, 3.60s2H, 4.42s4H,                                                    5.02s1H, 5.27s2H,                                                    1698.    6.70brs1H, 7.27-7.33m10H.              25 "      "        STetr.                                                                             "  --   --     3.40s3H, 3.60s2H, 3.80s3H,                                                    4.22s2H, 4.55s2H,                                                             5.00s1H, 5.27s2H, 6.55brs1H,                                                  7.25-7.33m10H.                         26 "      CHPh.sub.2                                                                             Cl   "  --   --     3.43s3H, 3.63s2H, 4.48s4H,                                                    5.07s1H, 6.40brs1H,                                                           6.92s1H, 7.23-7.60m15H.                27 "      "        STetr.                                                                             "  176-                                                                             3410,1792,1700.                                                                        3.42s3H, 3.60s2H, 3.67s3H,                                                    4.17s2H, 4.53brs2H,                                               178         5.02s1H, 6.77brs1H, 6.87s1H,                                                  7.17-7.50m15H.                         28 7-amino                                                                              CH.sub.2 Ph                                                                            "    "  --   --     3.43s3H, 3.80s3H, 4.23s2H,                                                    4.62s2H, 4.82s1H,                         derv.                               5.30s2H, 7.32m5H, 2.25brs2H.           29 "      CHPh.sub.2       -- 3360,3300,1770,                                                                        3.33br2H, 3.45s3H, 4.31brs2H,                                                 5.1-5.5m4H,                                                          1740,1600.                                                                             6.88s1H, 7.1-7.7m10H.                  30 "      "        STetr.                                                                             Δ.sup.3                                                                    149-                                                                               --     --                                                                150                                                31 pClC.sub.6 H.sub.4                                                                   "        "    "  --   --     3.60s3H, 3.77s3H, 4.25s2H,                                                    4.63s2H,                                                                      5.15s1H, 6.92s1H, 7-8m14H.             32 pNCC.sub.6 H.sub.4                                                                   "        "    "  -- 3425,2230,1790,                                                                        3.63s3H, 3.73s3H, 4.25brs2H,                                                  5.17brs2H, 5.17s1H,                                                  1721,1693,1632.                                                                        6.92s1H, 7.2-8.3m14H.                  33 pO.sub.2 NC.sub.6 H.sub.4                                                            "        "    "  -- 1790,1725,1695.                                                                        3.65s3H, 3.80s3H, 4.25s2H,                                                    4.66s2H, 5.16s1H,                                                             6.88s1H, 7.1-8.4m14H.                  34 pCH.sub.3 C.sub.6 H.sub.4                                                            "        "    "  -- 1788,1720,1683.                                                                        2.38s3H, 3.60s3H, 3.76s3H,                                                    4.26s2H, 4.61s2H,                                                             5.16s1H, 6.91s1H, 6.96s1H,                                                    7.1-7.9m14H.                           35 Ph     CH.sub.2 C.sub.6 H.sub.4 CH.sub.3 p                                                    "    "  -- 3420,1780,1718,                                                                        2.33s3H, 3.56s3H, 3.83s3H,                                                    4.25s2H, 4.58s2H,                                                    1680.    5.13s1H, 5.28s2H, 6.9-8.0m10H.         36 Ph     CH.sub.2 C.sub.6 H.sub.4 Clp                                                           "    "  -- 3425,1791,1729,                                                                        3.56s3H, 3.83s3H, 4.26s2H,                                                    4.60s2H, 5.11s1H,                                                    1690.    5.25s2H, 6.95s1H, 7.1-8.0m9H.          37 Ph     CH.sub.2 (naphthyl)                                                                    "    "  -- 3430,1790,1728,                                                                        3.58s3H, 3.80s3H, 4.25s2H,                                                    4.60s2H, 5.15s1H,                                                    1688.    5.85s2H, 6.98s1H,                      __________________________________________________________________________                                           7.2-8.3m12H.                       

EXAMPLE AA (ADDITION) ##STR58##

(Method)

According to the data on Table AA, an exomethylene compound (ii) in amixture of dichloromethane and ethyl acetate is mixed with a sulfenylchloride reagent (which may be prepared from e.g. (RS)₂ and chlorine),and permitted to react for given time at given temperature to give asulfide compound (iv).

EXAMPLE AA-1 (ADDITION-SUPPLEMENTS) ##STR59## R=--CH₃, R=Ph (1) R=--CH₃

To a solution of 7α-amino-3-methylene-1-dethia-1-oxacepham-4-carboxylicacid diphenylmethyl ester hydrochloride (1.0 g) in dichloromethane (10ml) is added a solution of methanesulfenyl chloride (6 molarequivalents) in dichloromethane (10 ml) under nitrogen atmosphere at-10° C., and the mixture is stirred for 40 minutes to afford a solutioncontaining7α-amino-3β-methylthio-3α-chloromethyl-1-dethia-1-oxacepham-4α-carboxylicacid diphenylmethyl ester hydrochloride. NMR: δ_(ppm) ^(CDCl).sbsp.31.67s2H, 2.13s2H.

To this solution are added propylene oxide (10 ml) and powderedMolecular Sieves (5 g). The mixture is stirred at room temperature for 1hour. Solid material is filtered off, and the filtrate is concentrated.Residue is purified by silica gel chromatography to give7-methylthioimino-3β-methylthio-3α-chloromethyl-1-dethia-1-oxacepham-4α-carboxylicacid diphenylmethyl ester (569 mg). Yield: 47% from the hydrochloride.IR: ν_(max) ^(CHCl).sbsp.3 1780, 1740 cm⁻¹.

(2) R=Ph

Under a condition similar to above (1), but substituting methanesulfenylchloride with phenylsulfenyl chloride, one obtains7-phenylthioimino-3β-phenylthio-3α-chloromethyl-1-dethia-1-oxacepham-4α-carboxylicacid diphenylmethyl ester (IR: ν_(max) ^(CHCl).sbsp.3 1780, 1740 cm⁻¹)in 48% yield through7α-amino-3β-phenylthio-3α-chloromethyl-1-dethia-1-oxacepham-4α-carboxylicacid diphenylmethyl ester (NMR: δ_(ppm) ^(CDCl).sbsp.3 1.80brs2H,4.60s1H.).

                                      TABLE AA                                    __________________________________________________________________________    Addition (Part 1)                                                              ##STR60##                                                                                                  CH.sub.3 CO                                                                        RSCl (iii)                                 exomethylene compound (ii)                                                                             CH.sub.2 Cl.sub.2                                                                  C.sub.2 H.sub.5 O                                                                  (RS).sub.2                                                                       CCl.sub.4                                                                        1MCl.sub.2 /                                                                       time                            No.                                                                              R    R.sup.1                                                                            E    B.sup.1                                                                           (g)                                                                              (ml) (ml) (ml)                                                                             (ml)                                                                             CCl.sub.4 (ml)                                                                     (min)                           __________________________________________________________________________    1  CH.sub.3                                                                           Ph   β-H                                                                           CHPh.sub.2                                                                        4.68                                                                             15   60   0.9                                                                              30 10   20                              2  CH.sub.3                                                                           tolyl                                                                              β-H                                                                           CHPh.sub.2                                                                        4.83                                                                             15   75   0.9                                                                              8.0                                                                              10   20                              3  CH.sub. 3                                                                          tolyl                                                                              α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        3.90                                                                             35   50   0.7                                                                              24 7.6  25                              4  CH.sub.3                                                                           thenyl                                                                             α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        1.04                                                                             10   --   0.2                                                                              5  2    20                                      malonyl                                                               5  CH.sub.3  α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        0.50                                                                             --   4    (0.61 mM CH.sub.3 SCl)                             PMB                                                                   6  Ph   Ph   β-H                                                                           CHPh.sub.2                                                                        7.0                                                                              30   100  3.27                                                                             25 15   20                              7  Ph   Ph   β-H                                                                           CH.sub.3                                                                          0.24                                                                              3   --   0.16                                                                             1.5                                                                              0.75 15                              8  Ph   tolyl                                                                              β-H                                                                           CHPh.sub.2                                                                        0.48                                                                              2   6    0.22                                                                             2.0                                                                              (SO.sub.2 Cl.sub.2)                                                                30                                                                       0.08                                 9  Ph   tolyl                                                                              α-CH.sub.3 O                                                                 0.33                                                                              10 20   0.33    4.0                                                                              1.5  20                              10 Ph   thenyl                                                                             α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        3.0                                                                              --   30   (16.9 mM Ph/SCl/CH.sub.2 Cl.sub.2 )                malonyl                                                               11 Ph        α-CH.sub.3 O                                                                 CHPH.sub.2                                                                        0.3                                                                              --   10   (1 eq. PhSCl/CH.sub.2 Cl.sub.2)                    PMB                                                                   __________________________________________________________________________                                  sulfide (i)                                                            temp                                                                             time                                                                              crop                                                                             yield                                                            No.                                                                              C.)                                                                              (min)                                                                             (g)                                                                              (%) IR: ν .sub.max.sup.CHCl.sub.3                                              cm.sup.-1                                __________________________________________________________________________                        1  rt 150 5.46                                                                             quant                                                                             3400, 1785, 1745, 1680                                       2  rt 120 6.05                                                                             92  mp. 182-183° C.                                       3  rt 150 3.90                                                                             85  NMR: 2.02s3H, 2.37s3H*                                       4  rt  90 1.03                                                                             76  3390, 1790, 1747, 1697                                       5  0   60 0.53                                                                             89  NMR: (1.96s + 1.98s)3H*                                      6  rt 120 8.08                                                                             88  3430, 1785, 1745, 1675                                       7  rt  60 0.16                                                                             46  3430, 1785, 1750, 1680                                       8  rt 300 0.47                                                                             75  mp. 218-219° C.                                       9  rt 180 1.21                                                                             93  mp. 211-212° C.                                       10 0  180 3.39                                                                             88  3380, 1780, 1740, 1695                                       11 rt 260 0.3                                                                              78  NMR: (3.40s + 3.41s)3H*                  __________________________________________________________________________     *NMR: δ.sub.ppm.sup.CDCl.sub.3                                     

EXAMPLE BB (ADDITION OF SELENYL) ##STR61##

(Method)

According to the data of Table BB, an exomethylene compound (ii) indichloromethane is mixed with a selenyl chloride reagent (iii) andpermitted to react for given time at given temperature to give aselenide (iv).

                                      TABLE BB                                    __________________________________________________________________________    Addition (Part 2)                                                              ##STR62##                                                                                             RScCl                                                exomethylene compound (ii)                                                       CH.sub.2 Cl.sub.2                                                                              (iii)                                                                              temp.                                                                             time                                                                              selenide (iv)                                No.                                                                              R R.sup.1                                                                          E    B.sup.1                                                                           (g)                                                                              (ml) (mg)                                                                              (°C.)                                                                      (min)                                                                             crop(g)                                                                           yield (%)                                                                          m.p.                            __________________________________________________________________________    1  Ph                                                                              Ph β-H                                                                           CHPh.sub.2                                                                        1.17                                                                             10   955 rt   90 1.44                                                                              87   160-161° C.              2  Ph                                                                              Ph β-H                                                                           H   0.15                                                                             4    120 0   240 0.60                                                                              --   TLC: Rf 0.28                                                                  (EtOAc;HOAc:H.sub.2                                                           O(16:1:1))/SiO.sub.2            3  Ph                                                                              tolyl                                                                            α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        0.26                                                                             4    191 rt  360 0.27                                                                              77   173-174° C.              __________________________________________________________________________

EXAMPLE CC (SUBSTITUTION) ##STR63##

(Method)

According to the data of Table CC, a chloromethyl compound (Iv) isdissolved in a mixture of methanol and acetone, mixed with1-methyl-5-tetrazolylthiol sodium salt dihydrate, and the mixture ispermitted to react at given temperature for given time to obtain a1-methyl-5-tetrazolylthio substituted product (vi).

                                      TABLE CC                                    __________________________________________________________________________    Substitution (Part 1)                                                          ##STR64##                                                                                                         NaSTetr     R.sup.2Substituted                                                            compound (vi)                halomethyl compound (iv) CH.sub.3 OH                                                                        CH.sub.3 COCH.sub.3                                                                  H.sub.2 O                                                                          temp                                                                             time                                                                              crop                                                                             yield                     No.                                                                              R    R.sup.1                                                                            E    B.sup.1                                                                           (g)                                                                              (ml) (ml)   (g)  (°C.)                                                                     (min)                                                                             (g)                                                                              (%)                                                                              IR:ν .sub.max.su                                                           p.CHCl.sbsp.3cm.sup                                                           .-1                    __________________________________________________________________________    1   CH.sub.3                                                                          Ph   β-H                                                                           CHPh.sub.2                                                                        2.20                                                                             40   20     1.40 refl                                                                             120 2.56                                                                             98 mp.                                                                           204-205°                                                               C.                     2  CH.sub.3                                                                           tolyl                                                                              β-H                                                                           CHPh.sub.2                                                                        1.00                                                                             20   10     0.66 refl                                                                             120 1.06                                                                             93 mp.                                                                           208-209°                                                               C.                     3  CH.sub.3                                                                           tolyl                                                                              α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        3.90                                                                             30   12     1.55 refl                                                                             20  5.03                                                                             98 NMR: 197s3H,                                                                  2.40s3H, 3.57s3H*      4  CH.sub.3                                                                           thenyl                                                                             α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        0.80                                                                             16   8      0.50 refl                                                                             40  0.89                                                                             98 3400, 1790,                                                                   1745, 1705                     malonyl                                        NMR: (1.88s +          5  CH.sub.3  α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        0.60                                                                             2.5  2.5    0.09 refl                                                                             30  0.53                                                                             92 1.92s)3H*                      PMB                                                                   6  Ph   Ph   β-H                                                                           CHPh.sub.2                                                                        1.23                                                                             20   10     0.70 refl                                                                             16 hr                                                                             0.97                                                                             70 mp.                                                                           175-176°                                                               C.                     7  Ph   thenyl                                                                             α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        1.00                                                                             10   10.7   0.42 refl                                                                             30 hr                                                                             0.66                                                                             59 3390, 1780,                                                                   1740, 1695                     malonyl                                        3400, 1780,            8  Ph        α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        0.14                                                                             0.7  0.7    0.03 refl                                                                             24 hr                                                                             -- 60 1735, 1720                     PMB                                                                   __________________________________________________________________________     *NMR: δ.sub.ppm.sup.CDCl.sbsp.3.                                   

EXAMPLE DD (SUBSTITUTION) ##STR65##

(Method)

According to the data of Table DD, a solution of a chloromethyl compound(iv) in a solvent is mixed with a nucelophilic reagent (v) (which can bethe same with the solvent), an acid scavenger (calcium carbonate, etc.)and a dehalogenating reagent (e.g. silver salt). The mixture is kept atthe given temperature for given time. The reaction mixture is worked upin a conventional manner to give a R² -substituted 1-dethia-1-oxacephamcompound (vi).

                                      TABLE DD                                    __________________________________________________________________________    Substitution (Part 2)                                                          ##STR66##                                                                                           nucleophilic silver                                    halomethyl compound (iv)                                                                             reagent (ml)                                                                           CaCO.sub.3                                                                        salt                                      No.                                                                              R  R.sup.1                                                                           E    B.sup.1                                                                           (mg)                                                                              solvent (ml)                                                                           (mg)                                                                              (mg)                                      __________________________________________________________________________    1  CH.sub.3                                                                         Ph  β-H                                                                           CHPh.sub.2                                                                        275 CH.sub.3 CO(CH.sub.3).sub.2                                                            150 AgBF.sub.4                                                       (3)          (196)                                     2  CH.sub.3                                                                         thenyl                                                                            α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        1200                                                                              CH.sub.3 CON(CH.sub.3).sub.2                                                           800 AgClO.sub. 4                                                     (20)         (920)                                     3  Ph thenyl                                                                            α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        800 CH.sub.3 CON(CH.sub.3).sub.2                                                           500 AgClO.sub.4                                                      (12)         (556)                                     4  CH.sub.3                                                                         Ph  β-H                                                                           CHPh.sub.2                                                                        275 CH.sub.3 COCH.sub.3 (2)                                                                150 AgBF.sub.4                                                       CH.sub.3 OH (4)                                                                            (196)                                     5  CH.sub.3                                                                         tolyl                                                                             α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        595 CH.sub.3 OH (6)                                                                        300 AgBF.sub.4                                                                    (390)                                     6  CH.sub.3                                                                         thenyl                                                                            α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        1900                                                                              CH.sub.3 OH (15)                                                                       300 AgClO.sub.4                                                                   (415)                                     7  CH.sub.3                                                                         tolyl                                                                             β-H                                                                           CHPh.sub.2                                                                        282 CH.sub.3 SOCH.sub.3                                                                    150 AgBF.sub.4                                                       H.sub.2 O    (196)                                     __________________________________________________________________________    temp   time                                                                              compound (vi)                                                      No.                                                                              (°C.)                                                                      (min)                                                                             R.sup.2                                                                              (mg)                                                                              (%) IR: ν .sub.max.sup.CHCl.sbsp.3                   __________________________________________________________________________                              cm.sup.-1                                           1  rt  180 CH.sub.3 COO                                                                         218 76  3435, 1785, 1750, 1683                              2  rt  210 CH.sub.3 COO                                                                         885 71  3400, 1790, 1750, 1695                              3  rt  24 hr                                                                             CH.sub.3 COO                                                                         559 67  3400, 1780, 1745, 1695                              4  rt  60  CH.sub.3 O                                                                           203 75  3425, 1778, 1743, 1672                              5  rt  90  CH.sub.3 O                                                                           585 99  NMR: 2.02s3H, 2.38s3Hppm*                           6  rt  90  CH.sub.3 O                                                                           1810                                                                              96  3400, 1783, 1743, 1695                              7  rt  60  HO     180 --  NMR: 2.00s3H, 2.32s3Hppm*                           __________________________________________________________________________     *NMR: δ.sub.ppm.sup.CDCl.sbsp.3                                    

EXAMPLE EE (OXIDATION AND ELIMINATION) ##STR67##

(Method)

According to the data on Table EE, a solution of a sulfide (vii) indichloromethane is mixed with m-chloroperbenzoic acid and the mixture iskept at given temperature for given time yielding the correspondingsulfoxide (viii) accompanied by a cephem type compound (x). The mixtureis refluxed for 30 minutes in acetone to give the cephem type compound(x) as a result of the elimination of a sulfenic acid from unreactedsulfoxide (viii). The reaction mixture is purified in a conventionalmanner to obtain a cephem type compound (x) in given yield.

                                      TABLE EE                                    __________________________________________________________________________    Oxidation and Elimination (Part 1)                                             ##STR68##                                                                                                                 cephem compound (x)              sulfide (vii)               CH.sub.2 Cl.sub.2                                                                  m-CPBA                                                                             temp                                                                             time            IR:ν .sub.max.                                                             sup.CHCl.sbsp.3      No.                                                                              R  R.sup.1                                                                           R.sup.2                                                                             E    B.sup.1                                                                           (mg)                                                                             (ml) (mg) (°C.)                                                                     (min)                                                                             (mg)                                                                             (%) mp.                                                                                 cm.sup.-1.)         __________________________________________________________________________    1  CH.sub.3                                                                         Ph  Cl    β-H                                                                           CHPh.sub. 2                                                                       200                                                                              6    64   0  30  124                                                                              68  amorph.                                                                            3440, 1793,                                                              powder                                                                             1732, 1675.          2  CH.sub.3                                                                         Ph  STetr β-H                                                                           CHPh.sub.2                                                                        180                                                                              3    57   0  15  151                                                                              90  203-205                                                                            3450, 1792,                                                                   1680.                3  CH.sub.3                                                                         Ph  CH.sub.3 COO                                                                        β-H                                                                           CHPh.sub.2                                                                        150                                                                              4    64   0  10  110                                                                              80  amorph.                                                                            3380br, 1785,                                                            powder                                                                             1735br, 1665.        4  Ph tolyl                                                                             Cl    β-H                                                                           CHPh.sub.2                                                                        150                                                                              6    58   0  20  132                                                                              quant                                                                             187-188                                                                            1775, 1743,                                                                   1668.                5  CH.sub.3                                                                         thenyl                                                                            CH.sub.3 COO                                                                        α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        500                                                                              6    180  0  15  417                                                                              90  175-176                                                                            3400, 1790,                                                                   1705.                6  CH.sub.3                                                                         thenyl                                                                            CH.sub.3 COO                                                                        α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        312                                                                              6    110  0  30  235                                                                              82  amorph.                                                                            3400, 1793,                                                              powder                                                                             1736, 1701.          7  Ph thenyl                                                                            STetr α-CH.sub.3 O                                                                 CHPh.sub.2                                                                         86                                                                              0.9  40   0  40  -- 79  175-176                                                                            3400, 1790,                                                                   1705.                __________________________________________________________________________

EXAMPLE FF (OXIDATION AND ELIMINATION) ##STR69##

(Method)

According to the data on Table FF, a sulfide (vii) is dissolved inacetone, mixed with 5N-peracetic acid and the mixture kept at the giventemperature for given time to afford a mixture of sulfoxide (viii: cf.Table I) and a cephem type compound (x). This is mixed with a smallamount of dimethyl sulfide to decompose excess reagent and the resultingmixture is refluxed to give a cephem type compound (x) formed byelimination of the sulfenyl group from the sulfoxide compound (viii).

                                      TABLE FF                                    __________________________________________________________________________    Oxidation and Elimination (Part 2)                                             ##STR70##                                                                    __________________________________________________________________________     sulfide (vii)                (CH.sub.3).sub.2 CO                                                                   ##STR71##                                                                           temp                                                                             time                           No.                                                                              R  R.sup.1                                                                            R.sup.2                                                                             E    B.sup.1                                                                           (mg)                                                                             (ml)    (ml)  (°C.)                                                                     (min)                           __________________________________________________________________________    1  CH.sub.3                                                                         Ph   STetr β-H                                                                           H   232                                                                              vide infra**   0 60                              2  CH.sub.3                                                                         tolyl                                                                              STetr β-H                                                                           H   478                                                                              12      0.3   rt 50                              3  Ph Ph   STetr β-H                                                                           H   360                                                                              2       0.4   0  50                              4  CH.sub.3                                                                         tolyl                                                                              STetr α-CH.sub.3 O                                                                 H   254                                                                              6       0.15  0  50                                                           HCON(CH.sub.3).sub.2                             5  CH.sub.3                                                                         thenyl                                                                             STetr α-CH.sub.3 O                                                                 H   200                                                                              25      0.24  0  20                              6  CH.sub.3                                                                         thenyl                                                                             CH.sub.3 COO                                                                        α-CH.sub.3 O                                                                 H   230                                                                              2       0.25  0  30                              7  CH.sub.3                                                                         malonyl                                                                            STetr α-CH.sub.3 O                                                                 H   212                                                                              4       0.3   0  60                                                           CH.sub.3 COOC.sub.2 H.sub.5                      8  Ph thenyl                                                                             Cl    α-CH.sub.3 O                                                                 CHPh.sub.2                                                                        2009                                                                             2             0  30                              9  Ph thenyl                                                                             STetr α-CH.sub.3 O                                                                 H   84 2.5     0.16  0  30                              10 Ph thenyl                                                                             STetr α-CH.sub.3 O                                                                 H   212                                                                              4       1 eq. 0  60                              11 Ph thenyl                                                                             CH.sub.3 COO                                                                        α-CH.sub.3 O                                                                 H   105                                                                              1       0.16  0  60                              __________________________________________________________________________                       cephem compound (x)                                                        No.                                                                               crop (mg)                                                                          (%)                                                                              mg (°C.)                                                                    IR: ν .sub.max.sup.CHCl.sbsp.3                                             cm.sup.-1 *                                  __________________________________________________________________________                    1  168   81 amorph.                                                                            3300, 1780, 1710, 1640 (Nujol)                                           powder                                                            2  236   55 151-152                                                                            --                                                           3   97   34 amorph.                                                                            3300, 1780, 1710, 1640 (Nujol)                                           powder                                                            4  243   88 amorph.                                                                            TLC: Rf 0.45 & 0.36 HOAc/EtOAc                                           powder                                                                             /water (8:1:1)                                               5  105   55 95-98                                                                              3200, 1785, 1695 (Nujol).                                    6  123   60 amorph.                                                                            3400, 1790, 1740, 1705.                                               powder                                                               7  147   76 129-135                                                                            1780, 1719, 1632 (KBr).                                      8  131   79 162-164                                                                            3400, 1785, 1725, 1695.                                      9   48   79 95-98                                                                              3200, 1785, 1695 (Nujol).                                    10 --    76 129-135                                                                            1780, 1719, 1632 (KBr)                                       11  56   68 amorph.                                                                            3400, 1790, 1740, 1705.                                                  powder                                            __________________________________________________________________________     *unless otherwise specified.                                                  ** 80% acetone 6 ml/Na.sub.2 WO.sub.4 2H.sub.2 O 20 mg/30% H.sub.2 O.sub.     aq 300 mg/NaHCO.sub.3 84 mg.                                             

EXAMPLE FF-1 (OXIDATION AND ELIMINATION: SELENYL) ##STR72##

To a solution of7α-benzamido-3β-phenylselenyl-3α-chloromethyl-1-dethia-1-oxacepham-4α-carboxylicacid diphenylmethyl ester (132 mg) in dichloromethane (3 ml) is addedm-chloroperbenzoic acid (49 mg) under ice cooling, and the mixture ispermitted to react for 10 minutes. The reaction mixture is poured intoaqueous sodium thiosulfate and extracted with ethyl acetate. The extractsolution is washed with aqueous sodium hydrogen carbonate and water,dried over sodium sulfate and concentrated under reduced pressure. Theresidue is purified by silica gel chromatography to give7α-benzamido-3-chloromethyl-1-dethia-1-oxa-3-cephem-4-carboxylic aciddiphenylmethyl ester (63 mg).

IR: λ_(max) ^(CHCl).sbsp.3 3340, 1793, 1732, 1675 cm⁻¹.

EXAMPLE GG (OXIDATION AND ELIMINATION) ##STR73##

(Method)

According to the data on Table GG, a sulfide (vii) is permitted to reactwith m-chloroperbenzoic acid in dichloromethane at given temperature forgiven time to give a sulfone (ix), and then the sulfone is treated witha strong base in dichloromethane to afford a cephem type compound (x).

                                      TABLE GG                                    __________________________________________________________________________    Oxidation and Elimination (Part 3)                                            __________________________________________________________________________     ##STR74##                                                                       sulfide (vii)                                                                             CH.sub.2 Cl.sub.2                                                                  m-CPBA                                                                             temp.                                                                             time                                                                              sulfone (xi)                                 No.                                                                              R.sup.1                                                                           E    (mg)                                                                             ml   (mg) (°C.)                                                                      (min)                                                                             crop (mg)                                                                           IR: ν .sub.max.sup.CHCl.sbsp.3                                             cm.sup.-1                              __________________________________________________________________________    1  Ph  β-H                                                                           200                                                                              4    126  0   30  190   3425, 1785, 1742, 1672.                2  thenyl                                                                            α-CH.sub.3 O                                                                 300                                                                              2    200  0   40  234   3400, 1790, 1745, 1700.                3  tolyl                                                                             α-CH.sub.3 O                                                                 200                                                                              1.5  140  0   15  196   NMR: δ .sub.ppm.sup.CDCl.sbsp                                           .3 2.33s3H, 2.88s3H.                   __________________________________________________________________________     ##STR75##                                                                       sulfone (ix)                                                                              CH.sub.2 Cl.sub.2                                                                  DBU* temp.                                                                             time                                                                              cephem type compound (x)                     No.                                                                              R.sup.1                                                                           E    (mg)                                                                             (ml) (μl)                                                                            (°C.)                                                                      (min)                                                                             crop (mg)                                                                           IR: ν .sub.max.sup.CHCl.sbsp.3                                             cm.sup.-1                              __________________________________________________________________________    1  Ph  β-H                                                                           150                                                                              1    75   -20 40  116   3430, 1790, 1725, 1673.                2  thenyl                                                                            α-CH.sub.3 O                                                                 230                                                                              2.5  82   -30 25  144   3420, 1790, 1725,                      __________________________________________________________________________                                           1700.                                   *DBU = 1,5diazabicyclo[4,5,0]undecene-5.                                 

EXAMPLE HH (EXCHANGE OF A AND B)

(I) Deacylation in A: ##STR76##

To a solution of7α-benzamido-3β-methylthio-3α-(1-methyl-5-tetrazolyl)thiomethyl-1-dethia-1-oxacepham-4α-carboxylicacid diphenylmethyl ester (160 mg) in chloroform (1.5 ml) is added asolution of pyridine (40 μl) and phosphorus pentachloride (51 mg) indichloromethane (1.0 ml) in nitrogen under ice cooling. After stirringfor 2 hours under ice cooling, the mixture is diluted with methanol 5ml) and stirred for 2 hours under ice cooling. The reaction mixture ispoured onto ice water containing sodium hydrogen carbonate and extractedwith dichloromethane. The extract solution is washed with water, driedon sodium sulfate and concentrated in vacuum to give7α-amino-3β-methylthio-3α-(1-methyl-5-tetrazolyl)thiomethyl-1-dethia-1-oxacepham-4α-carboxylicacid diphenylmethyl ester. TLC: Rf:=0.30 (C₆ H₆ -CH₃ COOC₂ H₅(1:1)/SiO₂)

Similarly prepared are7α-amino-3β-methylthio-3α-chloromethyl-1-dethia-1-oxacepham-4α-carboxylicacid diphenylmethyl ester (NMR: δ_(ppm) ^(CDCl).sbsp.3 1.67s2H, 2.13s3H,4.18s1H) and7α-amino-3β-phenylthio-3α-chloromethyl-1-dethia-1-oxa-cepham-4α-carboxylicacid diphenylmethyl ester (NMR: δ_(ppm) ^(CDCl).sbsp.3 1.80brs2H,4.25brs1H, 4.60s1H).

(II) Acylation at A: ##STR77##

To a solution of7α-amino-3β-methylthio-3α-(1-methyl-5-tetrazolyl)thiomethyl-1-dethia-1-oxacepham-4-carboxylicacid diphenylmethyl ester (180 mg) in dichloromethane (6 ml) are added2-p-methoxybenzyloxyphenyl-2-p-methoxybenzyloxycarbonylacetyl chloride(3.0 mg) and pyridine (0.06 ml), under nitrogen with stirring with icecooling. After stirring for 30 minutes, the reaction mixture is pouredonto ice water and extracted with ethyl acetate. The extract solution iswashed with aqueous sodium hydrogen carbonate and water dried oversodium sulfate and concentrated under reduced pressure. The residue ispurified by silica gel chromatography to give7α-(2-p-methoxybenzyloxyphenyl-2-p-methoxybenzyloxycarbonylacetyl)amino-3β-methylthio-3α-(1-methyl-5-tetrazolyl)thiomethyl-1-dethia-1-oxacepham-4α-carboxylicacid diphenylmethyl ester (252 mg). Yield: 53%.

NMR: δ_(ppm) ^(CDCl).sbsp.3 1.93s3H, 3.48s2H, 3.53s2H.

(III) Salt formation at COB: ##STR78##

(1) (Z=Na) To a solution of7α-benzamido-3β-methylthio-3α-(1-methyl-5-tetrazolyl)thiomethyl-1-dethia-1-oxacepham-4α-carboxylicacid in 0.1N-aqueous sodium carbonate is made pH 7.0. The mixed solutionis lyophilized to give the corresponding sodium salt.

NMR: δ_(ppm) ^(D).sbsp.2^(O) 2.02s3H, 4.05s3H, 5.03s1H.

(2) (Z=C₅ H₅ N.H) A solution of7α-benzamido-3β-methylthio-3α-(1-methyl-5-tetrazolyl)thiomethyl-1-dethia-1-oxacephem-4α-carboxylicacid in pyridine is concentrated to give the corresponding pyridiniumsalt.

NMR: δ_(ppm) ^(CDCl).sbsp.3 2.17s3H, 3.97s3H, 4.13s2H, 4.99s1H.

(IV) Esterification at COB: ##STR79##

To a solution of7α-benzamido-1-dethia-1-oxa-3β-phenylthio-3α-chloromethylcepham-4α-carboxylicacid (150 mg) in acetone (5 ml) is added a solution of diazomethane inether. After 5 minutes reaction, the mixture is concentrated underreduced pressure to dryness. The residue is crystallized from ether togive the corresponding methyl ester (123 mg). mp. 181°-182° C.

(V) Deesterification at COB ##STR80##

According to the data of Table HH, diphenylmethyl ester (xii) isdissolved in dichloromethane, mixed with trifluoroacetic acid andanisole and then let react for given time at given temperature. Byremoving solvent, reagent and by-products by a conventional manner, oneobtains the corresponding free acid (xiii) as solid material aftertrituration in ether.

                                      TABLE HH                                    __________________________________________________________________________    Free acid                                                                      ##STR81##                                                                     ester (xii)                CH.sub.2 Cl.sub.2                                                                  ##STR82##                                                                         ##STR83##                                                                         temp                                                                             time                              No.                                                                              R    R.sup.1                                                                            R.sup.2                                                                             E    (mg)                                                                             (ml) (ml)                                                                              (ml)                                                                              (°C.)                                                                     (min)                              __________________________________________________________________________    1  CH.sub.3                                                                           Ph   STetr β-H                                                                           1400                                                                             10   2   2   rt 90                                 2  CH.sub. 3                                                                          Ph   CH.sub.3 COO                                                                        β-H                                                                           300                                                                              2    0.5 0.5 0  90                                 3  CH.sub.3                                                                           thenyl                                                                             CH.sub.3 COO                                                                        α-CH.sub.3 O                                                                 850                                                                              4    0.8 0.8 0  120                                4  CH.sub.3                                                                           thenyl                                                                             CH.sub.3 O                                                                          α-CH.sub.3 O                                                                 550                                                                              4    0.8 0.8 rt 120                                5  CH.sub.3                                                                           thenyl                                                                             STetr α-CH.sub.3 O                                                                 300                                                                              2    0.4 0.4 rt 90                                         malonyl                                                               6  CH.sub.3  STetr α-CH.sub.3 O                                                                 532                                                                              5.3  1.06                                                                              1.06                                                                              0  1080                                       PNB                                                                   7  CH.sub.3                                                                           tolyl                                                                              STetr β-H                                                                           639                                                                              6    1   1   rt 90                                 8  CH.sub.3                                                                           tolyl                                                                              STetr α-CH.sub.3 O                                                                 1500                                                                             10   1.5 1.5 rt 90                                 9  Ph   Ph   Cl    β-H                                                                           1000                                                                             8    1.5 1.5 rt 40                                 10 Ph   Ph   STetr β-H                                                                           450                                                                              4    1   1   rt 90                                 11 Ph   thenyl                                                                             Cl    α-CH.sub.3 O                                                                 1023                                                                             10   2   2   rt 240                                12 Ph   thenyl                                                                             STetr α-CH.sub.3 O                                                                 228                                                                              2.9  0.58                                                                              0.58                                                                              0  240                                13 Ph   thenyl                                                                             CH.sub.3 COO                                                                        α-CH.sub.3 O                                                                 444                                                                              4    0.8 0.8 rt 60                                         malonyl                                                               14 Ph        STetr α-CH.sub.3 O                                                                 135                                                                              2    2   2   rt 90                                         PNB                                                                   __________________________________________________________________________                          free acid (xiii)                                                           No.                                                                              crop (mg)                                                                           (%)   1R: ν .sub.max.sup.Nujol                 __________________________________________________________________________                                      cm.sup.-1                                                      1  1090  quant mp. 194-195° C.                                         2  228   quant 3350, 1780, 1748, 1633                                         3  593   95    3400, 1785, 1750, 1700                                         4  279   70    3400, 1785, 1740-1690                                          5  224   quant mp. 222-223° C.                                           6                                                                              228    93*  mp. 110° C.                                               7                                                                              447   94    mp. 204-206° C.                                         8  714   65    NMR: 2.07s3H, 2.38s3H*                                         9  686   94    mp. 125-127° C.                                         10 341   quant 3400-3100, 1700, 1740                                          11 752   98    3400, 1780, 1735, 1695                                         12 145   65    mp. 190-205° C.                                         13 311   92    3400, 1780, 1745, 1700                                           14                                                                             51     55*  3200, 1770, 1730, 1680                      __________________________________________________________________________     *p-methoxybenzyl group is removed during the reaction.                        **NMR: δ.sub.ppm.sup.CD.sbsp.3.sup.COCD.sbsp. 3                    

                                      TABLE II                                    __________________________________________________________________________     ##STR84##                                                                                              TLC                                                 No.                                                                              R  R.sup.1                                                                            R.sup.2                                                                             E    B.sup.1                                                                           Rf       Developing solvent                         __________________________________________________________________________                                0.10                                              1  CH.sub.3                                                                         tolyl                                                                              STetr β-H                                                                           H         *  CH.sub.3 COOC.sub.2 H.sub.5CH.sub.3                                           COOHH.sub.2 O (16:1:1)                                                 0.08                                                                          0.45                                              2  CH.sub.3                                                                         tolyl                                                                              STetr α-CH.sub.3 O                                                                 H         *  CH.sub.3 COOC.sub.2 H.sub.5CH.sub.3                                           COOHH.sub.2 O (8:1:1)                                                  0.36                                              3  CH.sub.3                                                                         thenyl                                                                             CH.sub.3 COO                                                                        α-CH.sub.3 O                                                                 H     0.20   CH.sub.3 COOC.sub.2 H.sub.5CH.sub.3                                           COOHH.sub.2 O (16:1:1)                     4  CH.sub.3                                                                         malonyl                                                                            STetr α-CH.sub.3 O                                                                 H     0.63   CH.sub.3 COCH.sub.3CH.sub.3 COOHH.sub.2                                        O (95:5:10)                               5  Ph Ph   STetr β-H                                                                           H     0.64   CH.sub.3 COOC.sub.2 H.sub.5CH.sub.3                                           COOHH.sub.2 O (8:1:1)                      6  CH.sub.3                                                                         Ph   STetr β-H                                                                           CHPh.sub.2                                                                          0.085  C.sub.6 H.sub.6CH.sub.3 COOC.sub.2                                            H.sub.5 (9:1)                              7  Ph thenyl                                                                             STetr α-CH.sub.3 O                                                                 H     0.50   CH.sub.3 COOC.sub.2 H.sub.5CH.sub.3                                           COOHH.sub.2 O (8:1:1)                      8  Ph thenyl                                                                             CH.sub.3 COO                                                                        α-CH.sub.3 O                                                                 H     0.23   CH.sub.3 COOC.sub.2 H.sub.5CH.sub.3                                           COOHH.sub.2 O (16:1:1)                     9  Ph thenyl                                                                             STetr α-CH.sub.3 O                                                                 CHPh.sub.2                                                                          0.28   C.sub.6 H.sub.6CH.sub.3 COOC.sub.2                                            H.sub.5 (2:1)                              10 Ph thenyl                                                                             Cl    α-CH.sub.3 O                                                                 CHPh.sub.2                                                                          0.36   C.sub.6 H.sub.6CH.sub.3 COOC.sub.2                                            H.sub.5 (2:1)                              11 Ph malonyl                                                                            STetr α-CH.sub.3 O                                                                 H     0.57   CH.sub.3 COCH.sub.3CH.sub.3 COOHH.sub.2                                        O (95:5:10)                               __________________________________________________________________________     * The two spots correspond to the stereoisomers in relation to sulfoxide      bond.                                                                    

What we claim is:
 1. A 7-(arylthio or alkylthio)imino-3-(arylthio oralkylthio)-3-halomethyl-1-dethia-1-oxacepham-4α-carboxylic acid compoundof the following formula ##STR85## wherein R is C₁ to C₃ alkyl ormonocyclic aryl,COB is carboxy or protected carboxy, and Hal is ahalogen.
 2. A compound according to claim 1 wherein R is methyl orphenyl.
 3. A compound according to claim 1 wherein Hal is chlorine.